FR2932484A1 - NOVEL PYRROLOINDOLE DERIVATIVES INHIBITORS OF HSP90, COMPOSITIONS CONTAINING SAME AND USE THEREOF - Google Patents

Abstract

The invention relates to novel products of formula (I): ## EQU1 ## where Het represents an aromatic heterocycle or partially unsaturated, mono or bicyclic, containing from 1 to 4 N, O or S heteroatoms, optionally substituted with the same or different R1 or R'1; R is X- (AB) n-CONH2, X- (AB) n0-CONH2, X- (AB) n-NH-CONH2, X- (CH2) m -heterocycloalkyl, X- (CH2) m-aryl and X - (CH 2) m -heteroaryl with X is -OC (O), -NH-C (O), NH-CS, -NH-CO-CH 2 -O-; -NH-CO-CH 2 -S-CH 2 -CO-NH-; -NH-CO- (CH 2) 2 -SO 2 -; -NH-CO-CH 2 -N (CH 3) -CO-; A and B, which are identical or different, independently represent a single bond, CH 2, CH-alkyl, CH-aralkyl, n = 1.2 and m = 0.1; R1 and / or R'1 represent H, halogen, CF3, nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxy free or esterified with an alkyl radical, carboxamide, CO-NH (alkyl ), CON (alkyl) 2, NH-CO-alkyl, sulfonamide, NH-SO 2 -alkyl, S (O) 2 -NHalkyl, S (O 2) -N (alkyl) 2, all of these alkyl, alkoxy and alkylthio radicals being themselves possibly substituted; these products being in all isomeric forms and salts as medicaments.

Description

The present invention relates to novel chemical compounds, heterocyclic derivatives of pyrrolo [1,2-a] indole, compositions containing them, and their use as medicaments. BACKGROUND OF THE INVENTION More particularly, the invention relates, according to a first aspect, to novel heterocyclic pyrrolo [1,2-a] indole derivatives exhibiting anticancer activity, and in particular to an inhibitory activity of the Hsp90 chaperone protein, and more particularly via the inhibition of the ATPase catalytic activity of the chaperone Hsp90 protein.

Chaperone Proteins: The molecular chaperones of the Heat Shock Proteins (HSPs) family, classified according to their molecular weight (Hsp27, Hsp70, Hsp90 ...), are key elements of the balance between synthesis and degradation of cellular proteins, responsible for the correct folding of proteins. They play a vital role in response to cellular stress. HSPs, and in particular Hsp90, are also involved in the regulation of various major functions of the cell, via their association with various client proteins involved in cell proliferation or apoptosis (Jolly C. and Morimoto RI, JN Cancer Inst. (2000), 92, 1564-72, Smith DF et al., Pharmacological Rev. (1998), 50, 493-513, Smith DF, Molecular Chaperones in the Cell, 165-178, Oxford University Press 2001).

Chaperone Hsp90 and Hsp90 Inhibitors for the Treatment of Cancers: The Hsp90 chaperone, which represents 1 to 2% of the protein content of the cell, has recently been identified as a particularly promising target in cancer therapy (see for review: Moloney A. and Workman P., Expert Opin Biol Ther (2002), 2 (1), 3-24, Chiosis et al, Drug Discovery Today (2004), 9, 881-888). This interest is due in particular to the cytoplasmic interactions of Hsp90 with the main Hsp90 client 1 proteins, proteins that are involved in the six tumor progression mechanisms, as defined by Hanahan D. and Weinberg RA (Cell (2002), 100, 57-70), namely: a capacity to proliferate in the absence of growth factors: EGFR-5 R / HER2, Src, Akt, Raf, MEK, Bcr-Abl, Flt-3 ... - an ability to escape apoptosis: mutated form of p53, Akt, survivin

an insensitivity to proliferation stop signals: Cdk4, Plk, Weel ... an ability to activate angiogenesis: VEGF-R, FAK, HIF-1, Akt ... a capacity to proliferate without limit replicative: hTert ... - an ability to invade new tissues and to metastasize: c-Met Among the other Hsp90 client proteins, steroid hormone receptors, such as the estrogen receptor or the androgen receptor are also of great interest in the context of anti-cancer therapies. It has recently been shown that the alpha form of Hsp90 also has an extracellular role via its interaction with the metalloprotease MMP-2, itself involved in tumor invasion (Eustace BK et al, Nature Cell Biology (2004), 6). , 507-514). Hsp90 consists of two N- and C-terminal domains separated by a highly charged region. The dynamic interaction between these two domains, coordinated by the fixation of nucleotides and co-chaperones, determines the conformation of the chaperone and its activation state. The association of the client proteins mainly depends on the nature of the Hsp70 / Hsp40, Hop60, etc. co-chaperones and the nature of the ADP or ATP nucleotide linked to the N-terminal domain of Hsp90. Thus, the hydrolysis of ATP to ADP and the ADP / ATP exchange factor control the entire chaperone machinery, and it has been shown that it is sufficient to prevent hydrolysis of ATP to activity. ATPase of Hsp90 - to release into the cytoplasm the 30 client proteins which will then be degraded to the proteasome (Neckers L and Neckers K, Expert Opin., Emerging Drugs (2002), 7, 277-288; Neckers L, 2 Current Medicinal Chemistry). , (2003), 10, 733-739, Piper PW, Current Opin.Invest.New Drugs (2001), 2, 1606-1610).

Role of Hsp9O and its inhibitors in pathologies other than cancer: Various human pathologies are the consequence of incorrect folding of key proteins, leading in particular to neurodegenerative diseases following the aggregation of certain proteins as in diseases Alzheimer's and Huntington's or prion-related diseases (Tytell M. and Hooper PL, Emerging Ther, Targets (2001), 5, 267-287). In these pathologies, approaches to inhibit Hsp9O in order to activate stress pathways (Hsp7O for example) could be beneficial (Nature Reviews Neuroscience 6: 11, 2005). Some examples are given below: i) Huntinqton's disease: This neurodegenerative disease is due to an extension of CAG triplets in exon 1 of the gene encoding huntingtin protein. Geldanamycin has been shown to inhibit the aggregation of this protein due to overexpression of the Hsp7O and Hsp4O chaperones (Human Molecular Genetics 10: 1307, 2001). ii) Parkinson's disease: This disease is due to the progressive loss of dopaminergic neurons and characterized by the aggregation of the alpha-synuclein protein. Geldanamycin has been shown to be able to protect Drosophila from the toxicity of alpha-synuclein on dopaminergic neurons. iii) Focal cerebral ischemia: It has been shown in a rat animal model that geldanamycin protects the brain against cerebral ischemia, due to the effect of stimulating the transcription of the genes encoding heat. shock proteins by an Hsp90 inhibitor. Iv) Alzheimer's Disease and Multiple Sclerosis: These diseases are due in part to the expression of pro-inflammatory cytokines and the inducible form of NOS (Nitric oxide synthase) in the brain, and this expression of is suppressed by the stress response. In particular, Hsp9O inhibitors are able to harness this stress response, and it has been shown in vitro that geldanamycin and 17-AAG exhibit anti-inflammatory activity in brain glial cells (J. Neuroscience Res. 67: 461, 2002). v) Amyotrophic lateral sclerosis: This neurodegenerative disease is due to the progressive loss of motor neurons. Arimoclomol, an inducer of heatshock proteins, has been shown to delay the course of disease in an animal model (Nature Medicine 10: 402, 2004). Since an Hsp90 inhibitor is also an inducer of the heatshock proteins (Mol Cell Biol 19: 8033, 1999, Mol Cell Biol 18: 4949, 1998), it is likely that a beneficial effect could be expected. also obtained in this pathology for this type of inhibitors.

On the other hand, an inhibitor of the Hsp9O protein could be potentially useful in various diseases, other than the previously mentioned cancer, such as parasitic, viral, fungal, or neurodegenerative diseases, by direct action on Hsp9O and special customers. Some examples are presented below: vi) Malaria: Plasmodium falciparum Hsp9O protein has 59% identity and 69% similarity to human Hsp9O protein, and geldanamycin has been shown to inhibit parasite growth. in vitro (Malaria Journal 2: 30, 2003;

Biol. Chem. 278: 18336, 2003; J. Biol. Chem. 279: 46692, 2004). 4 vii) Bruqia and Bancroft filariasis: these lymphatic filarial parasites possess an Hsp9O protein that can potentially be inhibited by inhibitors of the human protein. In fact, it has been shown for another close parasite, Brugia pahangi, that the latter is sensitive to inhibition by geldanamycin. B. pahangi and human sequences are 80% identical and 87% similar. (Int. J. for Parasitology 35: 627, 2005) viii) Toxoplasmosis: Toxoplasma gondii, the parasite responsible for toxoplasmosis, has a chaperone protein Hsp9O, for which it has been shown induction during tachyzoite conversion. bradyzoite, corresponding to transition from chronic infection to active toxoplasmosis. In addition, geldanamycin blocks this tachyzoite-bradyzoite conversion in vitro (J. Mol Biol 350: 723, 2005) ix) Treatment-resistant mycoses: It is possible that the Hsp9O protein potentiates the evolution of drug resistance. , allowing new mutations to develop. Therefore, an inhibitor of Hsp9O, alone or in combination with other antifungal therapy, may be useful in the treatment of some resistant strains (Science 309: 2185, 2005). In addition, the anti-Hsp9O antibody developed by Neu Tec Pharma demonstrates activity against C. albicans, sensitive and resistant to fluconazole, C. krusei, C. tropicalis, C. glabrata, C. lusitaniae and C. parapsilosis in vivo ( Current Molecular Medicine 5: 403, 2005). x) Hepatitis B: Hsp9O is one of the host proteins that interacts with hepatitis B virus reverse transcriptase during the replication cycle of the virus. Geldanamycin has been shown to inhibit the replication of viral DNA and the encapsulation of viral RNA (Proc Natl Acad Sci USA 93: 1060, 1996) xi) Hepatitis C: Protein Human Hsp9O participates in the step of cleavage between the NS2 and NS3 proteins by the viral protease. Geldanamycin and radicicol are capable of inhibiting this NS2 / 3 cleavage in vitro (Proc Natl Acad Sci USA 98: 13931, 2001) xii) The Herpes Virus: Geldanamycin has demonstrated inhibition of HSV-1 replication in vitro, with a good therapeutic index (Antimicrobial Agents and Chemotherapy 48: 867, 2004). The authors also found geldanamycin activity on other HSV-2, VSV, Cox B3, HIV-1 and SARS coronavirus (data not shown). xiii) Denk (or tropical flu): It has been shown that the human Hsp9O protein participates in the entry stage of the virus, forming a complex also containing Hsp7O which serves as a receptor for the virus; An anti-Hsp9O antibody decreases the infectivity of the virus in vitro (J. of Virology 79: 4557, 2005) xiv) Spinal and Bulbar Muscular Atrophy (SBMA), an inherited neurodegenerative disease characterized by an extension of CAG triplets in the androgen receptor gene. 17-AAG, a derivative of Geldanamycin, has been shown to exhibit in vivo activity in transgenic animals as experimental models of this disease (Nature Medicine 11: 1088, 2005).

Hsp9O Inhibitors: The first known Hsp9O inhibitors are compounds of the amsamycin family, in particular Geldanamycin (1) and Herbimycin A. X-ray studies have shown that Geldanamycin binds to the ATP site of the N-terminal domain of Hsp9O where it inhibits the ATPase activity of chaperone (Prodromou C. et al, Cell (1997), 90, 65-75) Currently NIH and Kosan BioSciences are responsible for the clinical development of 17-AAG ( 2), which is a geldanamycin-derived Hsp9O inhibitor (1), which blocks the ATPase activity of Hsp90, by binding to the N-terminal recognition site of ATP. The results of Phase I clinical trials of 17-AAG (1) now lead to the initiation of phase II trials, but also orient research towards more soluble derivatives such as Kosan BioSciences analogue 3 (17-DMAG). ), carrying a dimethylamine chain in place of the methoxy residue, and to optimized 17AAG formulations (CNF1010 of Conforma Therapeutics): ## STR2 ## (1) 17-AAG (2) 17-DMAG (3) The reduced analogue of 17-AAG (WO2005063714 / US 2006019941) has also recently been in phase I clinical studies by Infinity Pharmaceuticals. Novel derivatives of geldanamycin or ansamycins have recently been described (WO2006016773 / US6855705 / US2005026894 / WO2006050477 / US2006205705 / WO2007001049 / WO2007064926 / WO2007074347 / WO2007098229 / WO2007128827 / WO2007128829). Radicicol (4) is also a naturally occurring Hsp90 inhibitor (Roe S.M. et al., J. Med Chem (1999), 42, 260-66). However, if it is by far the best in vitro inhibitor of Hsp90, its metabolic instability towards sulfur nucleophiles makes it difficult to use in vivo. Oxim derivatives much more stable such as KF 55823 (5) or KF 25706 were developed by Kyowa Hakko Kogyo (Soga et al, Cancer Research (1999), 59, 2931-2938) 7 Radicicol (4) OH HO HO Naturally related structures of radicicol have also been recently described, such as zearalenone (6) by Conforma Therapeutics (WO2003041643) or compounds (7-9). O Zearalenone 6) O-OH OH 8 7 Zearalanol acetate 9) HO HO Patent application US2006089495 discloses mixed compounds comprising a quinone ring, such as amsamycin derivatives, and a resorcinol ring, such as radicicol analogues, as inhibitors of Hsp90. A naturally occurring Hsp9O inhibitor, novobiocin (10) binds to a different ATP site located in the C-terminal domain of the protein (Itoh H. et al, Biochem J. (1999), 343, 697- 703). Recently, simplified analogs of Novobiocin have been identified as more potent Hsp9O inhibitors than Novobiocin itself (J. Amer Chem, Soc., 8 (2005), 127 (37), 12778-12779). Patent applications WO2006050501 and US2007270452 claim Novobiocine analogs as Hsp90 inhibitors. Patent application WO2007117466 claims Célastrol and Gédunine derivatives as Hsp90 inhibitors. A depsipeptide, named Pipalamycin or ICI101 has also been described as a noncompetitive inhibitor of the ATP site of Hsp90 (J. Pharmacol Exp Ther (2004), 310, 1288-1295). Sherperdine, a KHSSGCAFL nonapeptide, mimics part of the Survivin sequence K79-K90 (KHSSGCAFLSVK) and blocks the interaction of the IAP family proteins with Hsp90 in vitro (WO2006014744). Small peptides, including an Otoferline type sequence (YSLPGYMVKKLLGA), have recently been described as Hsp90 inhibitors (WO2005072766). Purines, such as PU3 compounds (11) (Chiosis et al., Chem Biol. (2001), 8, 289-299) and PU24FCI (12) (Chiosis et al., Curr. (12) Targets (2003), 3, 371-376, WO2002036075) have also been described as Hsp90 inhibitors: A purine derivative CNF2024 (13) has recently been introduced clinically by the company Conforma Therapeutics, in collaboration with the Sloan Kettering Memorial Institute for Cancer Research (W02006084030).

Patent application FR2880540 (Aventis) claims another family of Hsp90 inhibitory purines. Patent Application WO2004072080 (Cellular Genomics) claims a family of 8-heteroaryl-6-phenylimidazo [1,2-a] pyrazines as modulators of hsp90 activity. Patent Application WO2004028434 (Conforma Therapeutics) claims aminopurines, aminopyrrolopyrimidines, aminopyrazolopyrimidines and aminotriazolopyrimidines as Hsp90 inhibitors. Patent application WO2004050087 (RibotargetNernalis) claims a family of pyrazoles useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. Patent application WO2004056782 (Vernalis) claims a new family of pyrazoles useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. The patent application WO200407051 (Vernalis) claims arylisoxazole derivatives that are useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. Patent application WO2004096212 (Vernalis) claims a third family of pyrazoles useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. The patent application WO200500300 (Vernalis) more generally claims 5-membered heterocycles, substituted by aryl radicals, which are useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. Patent application JP2005225787 (Nippon Kayaku) claims another family of pyrazoles as Hsp90 inhibitors. Patent application WO200500778 (Kyowa Hakko Kogyo) claims a family of benzophenone derivatives as Hsp90 inhibitors, useful for the treatment of tumors. Patent application WO200506322 (Kyowa Hakko Kogyo) claims a family of resorcinol derivatives as Hsp90 inhibitors. Patent application WO2005051808 (Kyowa Hakko Kogyo) claims a family of resorcinylbenzoic acid derivatives as Hsp90 inhibitors. The patent applications WO2005021552, WO20050034950, WO200608503 WO2006079789 and WO2006090094 (Vernalis) claim families of pyrimidothiophenes or pyridothiophenes, useful for treating pathologies related to the inhibition of Heat Shock Proteins such as the Hsp9O chaperone. Application WO2006018082 (Merck) claims another family of pyrazoles as Hsp90 inhibitors. Application WO2006010595 (Novartis) claims a family of indazoles as Hsp90 inhibitors.

Application WO2006010594 (Novartis) claims a family of dihydrobenzimidazolones as Hsp90 inhibitors. The patent application WO2006055760 (Synta Pharma) claims a family of diaryl-triazoles as Hsp90 inhibitors. The patent application WO2006087077 (Merck) claims a family of (s-triazol-3-yl) phenols as Hsp90 inhibitors. The patent application FR2882361 (Aventis) claims a family of 3-aryl-1,2-benzisoxazoles as Hsp90 inhibitors. Patent Application WO2006091963 (Serenex) claims families of tetrahydroindolones and tetrahydroindazolone as Hsp90 inhibitors. The patent application DE10200509440 (Merck) claims a family of thienopyridines as Hsp90 inhibitors. Patent application WO2006095783 (Nippon Kayaku) claims a family of triazoles as Hsp90 inhibitors. The patent application WO2006101052 (Nippon Kayaku) claims a family of acetylenic derivatives as Hsp90 inhibitors. The patent application WO2006105372 (Conforma Therapeutics) claims a family of alkynyl pyrrolo [2,3-d] pyrimidines as Hsp90 inhibitors. The patent application FR2884252 (Aventis) claims a family of 5 isoindoles as Hsp90 inhibitors. Patent application WO20061009075 (Astex Therapeutics) claims a family of benzamides as Hsp90 inhibitors. Patent Application WO2006109085 (Astex Therapeutics) claims a family of hydroxybenzamides as Hsp90 inhibitors. The patent application WO2006113498 (Chiron) claims a family of 2-aminoquinazolin-5-ones as Hsp90 inhibitors. Patent application JP200606755 (Nippon Kayaku) claims a family of pyrazoles as Hsp90 inhibitors. The patent application WO2006117669 (Pfizer) claims a family of hydroxyarylcarboxamides as Hsp90 inhibitors. Patent applications WO2006122631 and DE102006008890 (Merck GmbH) claim a family of amino-2-phenyl-4-quinazolines as Hsp90 inhibitors. The patent application WO2006123061 (Aventis) claims a family of azabenzimidazolyl- or benzimidazolyl-fluorenes derivatives as Hsp90 inhibitors. Patent Application WO2006123065 (Astex Therapeutics) claims a family of azinamines (amino-2-pyrimidines or triazines) as Hsp90 inhibitors. The patent application WO2006125531 (Merck GmbH) claims a family of thieno [2,3b] pyridines as Hsp90 inhibitors. Patent applications WO2006125813 and WO2006125815 (Altana Pharma) claim a family of tetrahydropyridothiophenes as Hsp90 inhibitors. The patent application WO2007017069 (Merck GmbH) claims a family of adenine derivatives as Hsp90 inhibitors. Patent applications WO2007021877 and WO200701966 (Synta Pharma) respectively claim arylpyrazole and arylimidazole families as Hsp90 inhibitors. Patent application WO2007022042 (Novartis) claims a family of pyrimidylaminobenzamides as Hsp90 inhibitors. Patent application WO2007034185 (Vernalis) claims a family of heteroarylpurines as Hsp90 inhibitors. Patent application WO2007041362 (Novartis) claims a family of 2-amino-7,8-dihydro-6H-pyrido [4,3-d] pyrimidin-5-ones as Hsp90 inhibitors. Patent application WO2007104944 (Vernalis) claims a family of pyrrolo [2,3b] pyridines as Hsp90 inhibitors. The patent application US2007105862 claims a family of nitrogen derivatives as Hsp90 inhibitors. Patent application WO2007129062 (Astex Therapeutics) claims a family of diazoles (aryl pyrazoles) as Hsp90 inhibitors. US2007129334 (Conforma Therapeutics) claims a family of arylthio-purines as orally active Hsp90 inhibitors. Patent application WO2007155809 (Synta Pharma) claims families of phenyltriazoles as Hsp90 inhibitors. Patent Application WO2007092496 (Conforma Therapeutics) claims a family of 7,9-dihydropurin-8-ones as Hsp90 inhibitors. Patent application WO2007207984 (Serenex) claims a family of cyclohexylaminobenzene derivatives as Hsp90 inhibitors. Patent applications DE10206023336 and DE10206023337 (Merck GmbH) respectively claim families of 1,5-diphenylpyrazoles and 1,5-diphenyltriazoles as inhibitors of Hsp90. The patent application WO2007134298 (Myriad Genetics) claims a family of purinamines as Hsp90 inhibitors. Patent application WO2007138994 (Chugai) claims families of 2-aminopyrimidines or 2-aminotriazines as Hsp90 inhibitors. Patent applications WO2007139951, WO2007139952, WO2007139960, WO2007139967, WO2007139968, WO2007139955 and WO20071400002 (Synta Pharma) claim families of triazoles as Hsp90 inhibitors and agents for the treatment of non-Hodgkin's lymphomas.

The present invention relates to pyrrolo [1,2-a] indole derivatives of the formula (I) Het (I) in which: Het represents an aromatic or partially unsaturated heterocycle of dihydro or tetrahydro mono or bicyclic type; 5 to 11-membered ring containing 1 to 4 heteroatoms selected from N, O or S, optionally substituted with one or more identical or different RI or R'1 radicals as described below, R is selected from the group consisting of by X- (AB) n-CONH2, X- (AB) n-OCONH2, X- (AB) n-NH-CONH2, X- (CH2) m -heterocycloalkyl, X- (CH2) m-aryl and X- (CH 2) m -heteroaryl with X is -OC (O), -NH-C (O), NH-CS, -NHCO-CH 2 -O-; -NH-CO-CH 2 -S-CH 2 -CO-NH-; -NH-CO- (CH 2) 2 -SO 2 -; -NH-CO-CH2-N (CH3) -CO-; A and B, which are identical or different, independently represent a single bond, CH 2, CH-alkyl, CH-aralkyl, n = 1.2 and m = 0, 1, 14, 293, 244 R1 and / or R'1, which may be identical or different, are in the group consisting of H, halogen, CF3, nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxy free or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl) 2, NH-CO-alkyl, sulfonamide, NH-SO 2 -alkyl, S (O) 2 -NHalkyl, S (O 2) -N (alkyl) 2, all the alkyl, alkoxy and alkylthio radicals being themselves optionally substituted by one or more identical or different radicals selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomeric and diastereoisomeric, as well as as addition salts with mineral and organic acids or with the inorganic and organic bases of the products of formula (I) as well as the prodrugs of the products of general formula (I). In the products of formula (I) and in what follows, the terms indicated have the following meanings:

the term halogen denotes fluorine, chlorine, bromine or iodine atoms and preferably fluorine, chlorine or bromine atoms.

the term "alkyl radical" denotes a linear or branched radical containing at most 12 carbon atoms chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and secpentyl radicals, p-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and also heptyl, octyl, nonyl, decyl, undecyl and dodecyl, as well as their linear or branched positional isomers. Alkyl radicals having at most 6 carbon atoms and in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, linear or branched pentyl or linear or branched hexyl radicals are more particularly mentioned.

the term "alkoxy radical" denotes a linear or branched radical containing at most 12 carbon atoms and preferably 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, and pentoxy, hexoxy and heptoxy radicals; as well as their linear or branched positional isomers,

The term alkylthio or alkyl-S- denotes a linear or branched radical containing at most 12 carbon atoms and represents in particular the methylthio, ethylthio, isopropylthio and heptylthio radicals. In radicals containing a sulfur atom, the sulfur atom can be oxidized to a radical SO or S (0) 2

the term carboxamide denotes CONH2.

the term sulphonamide denotes SO2NH2. the term acyl radical or r-CO- denotes a linear or branched radical containing at most 12 carbon atoms in which the radical r represents a hydrogen atom, an alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl or aryl radical, these radicals having the values indicated above and being optionally substituted as indicated: mention is made for example of the radicals formyl, acetyl, propionyl, butyryl or benzoyl, or valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl;

the term "cycloalkyl radical" denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 ring members and in particular denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, the term "cycloalkylalkyl radical" denotes a radical in which cycloalkyl and alkyl are chosen from the values indicated above: this radical thus designates, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl radicals.

the term "acyloxy radical" means the acyl-O- radicals in which acyl has the meaning indicated above; for example, acetoxy or propionyloxy radicals are mentioned.

by acylamino radical is meant the acyl-N- radicals in which acyl has the meaning indicated above. The term "aryl radical" refers to unsaturated, monocyclic or fused carbocyclic rings. Examples of such an aryl radical include phenyl or naphthyl radicals.

Arylalkyl is understood to mean the radicals resulting from the combination of the alkyl radicals mentioned above which are optionally substituted and the aryl radicals also mentioned above, which are optionally substituted: for example, the benzyl, phenylethyl, 2-phenethyl, triphenylmethyl or naphthyleneemethyl radicals are mentioned.

the term "heterocyclic radical" denotes a saturated (heterocycloalkyl) or partially or totally unsaturated (heteroaryl) carbocyclic radical consisting of 4 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or of sulfur.

As heterocycloalkyl radicals, there may be mentioned in particular the radicals dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidyl, pyrrolidinyl, imidazolidinyl, imidazolidine-2,4-dione, pyrazolidinyl, morpholinyl or tetrahydrofuryl, hexahydropyran. , tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, perhydropyranyl, pyrindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl or thioazolidinyl, all of these radicals being optionally substituted.

Among the heterocycloalkyl radicals, mention may be made in particular of optionally substituted piperazinyl, N-methylpiperazinyl, piperidyl, optionally substituted, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, hexahydropyran or thiazolidinyl radicals.

By heterocycloalkylalkyl radical is meant radicals in which the heterocycloalkyl and alkyl radicals have the above meanings

among the 5-membered heteroaryl radicals, mention may be made of furyl, pyrrolyl, tetrazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thienyl and triazolyl radicals,

Among the 6-membered heteroaryl radicals, mention may be made especially of pyridyl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidyl, pyridazinyl and pyrazinyl radicals.

As condensed heteroaryl radicals containing at least one heteroatom selected from sulfur, nitrogen and oxygen, there may be mentioned for example benzothienyl, benzofuryl, benzopyrrolyl, benzothiazolyl, benzimidazolyl, imidazopyridyl, imidazopyrimidinyl, imidazopyrazinyl, purinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, thionaphthyl, chromenyl, indolizinyl, quinazolinyl, quinoxalinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl and naphthyridinyl.

The term "alkylamino radical" means the radicals in which the alkyl radical is chosen from the alkyl radicals mentioned above. Alkyl radicals having at most 4 carbon atoms are preferred and mention may be made, for example, of linear or branched methylamino, ethylamino, propylamino or butylamino radicals.

The term "dialkylamino radical" means the radicals in which the identical or different alkyl radicals are chosen from the alkyl radicals mentioned above. As previously, alkyl radicals having at most 4 carbon atoms are preferred, and for example linear or branched dimethylamino, diethylamino or methylethylamino radicals may be mentioned.

The term patient refers to humans but also to other mammals.

The term "prodrug" refers to a product that can be transformed in vivo by metabolic mechanisms (such as hydrolysis) into a product of formula (I). For example, an ester of a product of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to its parent molecule. Alternatively, an ester of a carboxy group-containing product of formula (I) can be converted by in vivo hydrolysis into its parent molecule.

By way of examples, mention may be made of hydroxyl group-containing esters of the formula (I), such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bisulfates and the like. b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, cyclohexylsulfamates and quinates.

Particularly useful hydroxyl-containing products of the formula (I) can be prepared from acidic residues such as those described by Bundgaard et al. al., J. Med. Chem., 1989, 32, page 2503-2507: these esters include in particular substituted (aminomethyl) -benzoates, dialkylamino-methylbenzoates in which the two alkyl groups can be bonded together or can be interrupted by an oxygen atom or by a optionally substituted nitrogen atom is an alkylated nitrogen atom or else morpholino-methyl) benzoates, eg 3- or 4- (morpholinomethyl) -benzoates, and (4-alkylpiperazin-1-yl) benzoates, eg 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

The carboxyl group (s) of the products of formula (I) may be salified or esterified.

It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism. The term stereoisomer is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above. The present invention thus relates in particular to the products of formula (I) as defined above in which Het represents a heterocycle as defined above containing in particular at least one nitrogen atom and optionally substituted with one or more RI radicals. or R'1 identical or different as defined above, and R having any of the definitions given above or below

said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomeric and diastereoisomeric, as well as as addition salts with mineral and organic acids or with the inorganic and organic bases of the products of formula (I) as well as the prodrugs of the products of general formula (I).

The present invention thus relates in particular to the products of formula (I) as defined above in which: Het is chosen from the group consisting of: ## STR1 ## ## STR2 ## - NNH RI and / or R'1 identical or different are in the group consisting of H, halogen, CF3, nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio (methylthio), free carboxy or esterified with an alkyl radical, carboxamide, CO-NH (alkyl) and CON (alkyl) 2, NH-CO-alkyl, sulfonamide, NH-SO 2 -alkyl, S (O) 2 -NH (alkyl), S (O) 2-N (alkyl) 2, all alkyl, alkoxy and alkylthio radicals being themselves optionally substituted by one or more identical or different radicals selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; the substituent R of said products of formula (I) being chosen from the values defined above or below, said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomers and diastereoisomers, as well as addition salts with the mineral and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the prodrugs of the products of general formula (I).

The present invention thus relates in particular to the products of formula (I) as defined above in which Het represents a heterocycle as defined above optionally substituted with one or more radicals RI or R'1 which are identical or different as defined herein. above, and R represents in particular the group X- (CH 2) m -heteroaryl as defined above or below with X represents in particular -NH-CO- and m represents in particular 0. said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomeric and diastereoisomeric, as well as as addition salts with inorganic and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the prodrugs of the products of general formula (I).

The present invention thus relates in particular to the products of formula (I) as defined above in which Het represents a heterocycle as defined above optionally substituted with one or more radicals R1 or R'1 which are identical or different as defined herein. above, and R is chosen from the group consisting of: wherein said products of formula (I) are in all possible tautomeric and isomeric forms, racemic, enantiomers and diastereoisomers, and also as addition salts with the inorganic and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the prodrugs of the products of general formula (I).

The present invention thus relates in particular to the products of formula (I) as defined above or below in which: Het is chosen from the group consisting of: ## STR1 ## selected from the group consisting of: MeO ~ / ~ s H2NN NH NH HH -.- NH NH R1 is in the group consisting of H, F, Cl, Br, CF3, NO2, CN, CH3, OH, OCH3, OCF3, CO2Me, CONH2, CONHMe, CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC (O) Me, SO2NH2, SO2N (Me) 2; R'1 is in the group consisting of H, CONH2, CONHMe and OMe; R "1 is in the group consisting of F, Cl, OH, OMe, CN, O- (CH2) 3-OMe and O- (CH2) 3 -N (Me) 2, said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomeric and diastereoisomeric, as well as as addition salts with mineral and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the product prodrugs of general formula (I).

The present invention thus relates in particular to the products of formula (I) as defined above or below in which: Het is chosen from the group consisting of: ## STR2 ## iy N

NNH R1 MeOre H2NNe R is selected from the group consisting of: R1 is in the group consisting of H, F, Cl, Br, CF3, NO2, CN, CH3, OH, OCH3, OCF3, CO2Me, CONH2, CONHMe, CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC (O) Me, SO2NH2, SO2N (Me) 2, R'1 is in the group consisting of H, CONH2, CONHMe and OMe, R "1 is in the group consisting of F, Cl, OH, OMe, CN, O- (CH2) 3-OMe and O- (CH2) 3 -N (Me) 2 said products of formula (I ) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral and organic bases.

The invention particularly relates to the products of formula (I) as defined above in which: Het is selected from the group consisting of: R1 with: R1 represents H, F, Cl, Br, CF3, NO2 , CN, CH3, OH, OCH3, OCF3, CO2Me, CONH2, CONHMe, CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC (0) Me, SO2NH2, SO2N (Me ) 2; R'1 represents H, CONH2, CONHMe and OMe; R "1 represents F, Cl, OH, OMe, CN, O- (CH2) 3-OMe and O- (CH2) 3-N (Me) 2, and R is selected from the group consisting of: NH - NH NH and their prodrugs, said products of formula (I) being in all possible isomeric forms tautomers, racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The present invention more particularly relates to the products of formula (I) as defined above, whose names follow: [5- (6-fluoro-1H-benzimidazol-2-yl) -9H-pyrrolo [ 1 H -pyrrolo [2,3-b] pyridine-4-carboxylic acid 1,2-a] indol-9-yl] amide. 1H-pyrrolo [2,3-b] pyrid-4- (5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-yl) -amide; carboxylic acid. [1- (3H-Imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide of 1H-pyrrolo acid [2,3-b] pyridine-4-carboxylic acid. 6-chloroacid [5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide; 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid. as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The products of formula (I) according to the present invention may be prepared according to the known methods of the invention. Those skilled in the art and particularly according to the methods described below: the subject of the present invention is also the methods of synthesis of the products of formula (I) according to the present invention and in particular the general methods of synthesis described in the following schemes .

General Synthesis Methods for Compounds of General Formula (I): The products of general formula (I) can be prepared from a derivative of general formula (II) or via a derivative of general formula ( III) (method A) or via a derivative of general formula (IV) (method B) according to the general scheme (1) below:

Het Het method B (IV) Z = OTf, I, Br, B (OH) 2 or B (OR) 2 * or C (O) -OMe, C (O) -OH or C (O) -H) or The present invention thus particularly relates to a process for the preparation of the products of formula (I) as defined above, characterized by the presence of a compound of formula (I). Scheme (I) above, according to which the products of general formula (I) can be prepared from a derivative of general formula (II), or via a derivative of general formula (III) ( method A) or via a derivative of general formula (IV) (method B) and in which the substituents Het and R have the meanings indicated above for the products of formula (I) and za the indicated meaning above in the diagram (1) ,.

The subject of the present invention is also the processes for the preparation of the products of formula (I), and intermediates making it possible to obtain products of formula (I), according to schemes 2 to 12 below.

Preparation of compounds of general formula (II) The present invention thus also relates to the methods of synthesis of the products of formula (II), in which Z represents bromine, triflate radical, boronic acid or boronate, optionally cyclic , a carboxy radical, a methyl carboxylate radical, the hydroxyl radical, or the benzyloxy radical. The product of general formula (II) in which Z represents the iodine atom can be obtained according to J. Med. Chem. 2004, 47 (6), 1448. The product of the general formula (II) in which Z represents the bromine atom can be obtained by replacing the iodine atom with the bromine atom in the previous process described in J. Med. Chem. 2004, 47 (6), 1448. The product of the general formula (II) in which Z represents the benzyloxy radical can be obtained according to the general methods known to those skilled in the art and in particular by adapting those described in FIG. .Org.Chem. 1967, 32 (2), 486. The product of general formula (II) in which Z represents the hydroxyl radical can be obtained by debenzylation according to the general methods known to those skilled in the art of the product of general formula ( II) in which z represents the benzyloxy radical. The product of general formula (II) in which Z represents the trifluoromethanesulfonyloxy radical (also called triflate in the following of the invention) can be obtained by the action of a trifluoromethylsulfonation agent, such as N-phenylbis (trifluoromethanesulfonimide). ), in an organic solvent such as dichloromethane, in the presence of an organic base such as triethylamine, according to scheme (2) below. (II) Z = OS (O) 2 CF 3 (OTF) Scheme (2) The product of general formula (II) in which Z represents a methyl carboxylate radical can be obtained either by a carbonylation reaction in methanol, catalyzed by a palladium complex such as palladium acetate in the presence of phosphine ligand such as 1,3-diphenylphosphinopropane, or by the cyclization reaction with BBr3 in dichloromethane from the dimethyl ester of the acid 2 (1-pyrrolyl) isophthalic described in Helv.Chim.Acta 1983, 66 (7), 2135, according to Scheme (3) below: MeOOC CO BBr3 Pd (OAc) MeOOC COOMe 0 Et, N / DMF / MeOH NI CH2Cl2 N

The product of the general formula (II) wherein Z represents a carboxy radical can be obtained by hydrolysis according to the general methods known to those skilled in the art. (Ph2P-CH2) 2-CH2 (Scheme (3)) art of the compound of general formula (II) wherein z represents a methyl carboxylate radical.

The product of general formula (II) in which Z represents a formyl radical can be obtained by operating according to the general methods known to those skilled in the art from the product of general formula (II) in which z represents the radical methyl carboxylate.

The product of general formula (II) in which z represents a chlorocarbonyl radical may be obtained by choriding the compound of general formula (II) in which z represents a carboxy radical according to the general methods known to those skilled in the art.

The products of general formula (II) in which Z represents a boronic acid or an optionally cyclic boronic ester may advantageously be prepared by the action of a lithiated base and then of a borate, such as trimethyl borate, tritium borate or borate. n-butyl or triisopropyl or pinacolyl diboronate, on 5-bromo-pyrrolo [1,2-a] indol-9-one at low temperature in an organic solvent such as tetrahydrofuran, or again from 5 -iodo- or 5-trifluoromethylsulfonyloxy-pyrrolo [1,2-a] indol-9-one, in the presence of a palladium (0) catalyst, according to scheme (4). (II) Z = B- (OH) 2, B (Oalk) 2 with Oalk = OMe, OnBu, OiPr (O) / Scheme (4) Preparation of Compounds of General Formula (III)

The present invention thus also relates to the methods of synthesis of the products of formula (III), in which, R 1 and / or R '1 being as defined above, Het is in the group consisting of: Br, I, OTf B (Oalk) 3 or (B (Oalk) 2) 2H (alkru-THF BH (alk) ## STR1 ## ## STR2 ## In particular, when Het does not represent a heterocyl of the imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, and is optionally substituted by one or more radicals R1, as defined above, it is particularly advantageous according to invention of preparing the compounds of general formula (III) either by coupling of a compound of general formula (II) wherein z represents an iodine atom, a bromine atom or the trifluoromethanesulfonyloxy radical with a boronic heterocyclic derivative, acid or ester, or by coupling a compound of general formula (II) in which z represents boronic acid or boronic ester, optionally cyclic - such as methyl, n-butyl, isopropyl or pinacol ester with a bromo or a iodo heterocycle, under the conditions of the Suzuki reaction, in the presence of of a palladium derivative (O) as a catalyst, according to scheme (5): OH (alk), B4OH (alk) 1 Het Het N "Pd (O) -1 Br (I) Het" Pd (0) (II) Z = I, Br, OTf (II) Z = B- (OH) 2, B (Oalk) Z Scheme (5) More particularly, when the heterocycle Het is benzimidazole or azabenzimidazole - or although again of the benzoxazole or azabenzoxazole, benzothiazole or azabenzothiazole type, linked by its 2-position to the 5-position of pyrrolo [1,2-a] indol-9-one, it is particularly advantageous to form said heterocycle by coupling a derived from orthophenylenediamine or diamino-pyridine - or ortho-aminophenol, orthoaminothiophenol or amino-hydroxy-pyridine or ortho-disubstituted amino-mercapto-pyridine - with an acid, an acid chloride, a methyl ester, or an aldehyde at the 5-position of pyrrolo [1,2-a] indol-9-one according to scheme (6): R1 ~~ AH V'NH2 1) coupling 2) cyclization A = NH2O, S

Z = COOH, COCI, COOMe, CHO V1 = N, CRI R1 as defined above

Scheme (6) When using the 5-carboxylic acid derivative of pyrrolo [1,2-a] indol-9-one, it is particularly advantageous to activate this acid with a known coupling agent. those skilled in the art, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in the presence of 1-hydroxybenzotriazole (HOBT), o - ((ethoxycarbonyl) cyanomethyleneamino tetrafluoroborate) - N, N, N ', N'-tetramethyluronium (TOTU) or o- (1H-benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU).

When a methyl ester derivative of the 5-carboxylic acid of pyrrolo [1,2-a] indol-9-one is used, it is advantageous in the context of the invention to operate in the presence of trimethylaluminium. in a halogenated organic solvent, such as dichloromethane or dichloroethane.

When a 5-carboxaldehyde derivative of pyrrolo [1,2-a] indol-9-one is used, it is advantageous, in the context of the invention, to operate: either by microwave heating in presence of silica, according to Tetrahedron Lett. 1998, 39, 4481-84; or in the presence of dichloro-dicyano-benzoquinone (DDQ), according to Tetrahedron 1995, 51, 5813-18; or in the presence of a mixture of thionyl chloride and pyridine, according to E.P. 511187; - in the presence of ferric chloride, according to Eur. J. Med. Chem. 10 2006, 31, 635-42. Various cyclization conditions of the mixture of intermediate amides can be used in the context of the invention, such as acetic acid or a mixture of acid and trifluoroacetic anhydride. It is also particularly advantageous in the context of the invention to carry out this type of thermal cyclization in an acid medium by heating in a microwave reactor.

More particularly, when said heterocycle is of the imidazole, oxazole or thiazole type, linked by its 2-position to the 5-position of pyrrolo [1,2-a] indol-9-one, it is particularly advantageous to form said heterocycle from an acid, an acid chloride, an ester or an aldehyde at the 5-position of pyrrolo [1,2-a] indol-9-one, according to the scheme (7 ): B 1) coupling 2) cyclization 'NH2 (II) A = NH2O, SB = AH or a precursor reactive group of A z = COOH, COCI, COOMe, CHO Scheme (7) Within the scope of the invention is particularly advantageous to operate: 1. in the case where said heterocycle is an imidazole or imidazoline: + optionally isolated 3) oxidation 32 - from a 2-azido-ethylamine, according to Tetrahedron, 47 (38), 1991 , 8177-94, - an ethylenediamine, according to Biorg. Med. Chem Lett. 12 (3), 2002, 471-75, - glyoxal and ammonia, according to J. Med. Chem., 46 (25), 2003, 5416-27; 2. in the case where said heterocycle is an oxazole or an oxazoline: - from a 2-azidoethanol, according to J. Org. Chem., 61 (7), 1996, 2487-96, 2-aminoethanol, according to J. Med. Chem. 47 (8), 2004, 1969-86 or Khim. Geterosiki. Soed. 1984 (7), 881-4, 2-aminoacetaldehyde diethyl acetal, according to Heterocycles, 39 (2), 1994, 767-78; 3. in the case where said heterocycle is thiazole or a thiazoline: - from a 2-chloro-ethylamine and Lawesson's reagent, according to Helv. Chia. Acta, 88 (2), 2005, 187-95, 2-aminoethanethiol, according to J. Org. Chem. 69 (3), 2004, 811-4, or Tetrahedron Lett., 41 (18), 2000, 3381-4. More generally, it is advantageous in the context of the invention to form the heterocycle of a product of general formula (III) from a triflate, a brominated or iodinated derivative, a boronic acid or ester, a carboxylic acid, an acid chloride , a carboxylic acid ester or an aldehyde, at the 5-position of pyrrolo [1,2-a] indol-9-one by any of the synthetic methods known to man of the art, such as those described in Comprehensive Organic Chemistry, by DHR Barton et al. (Pergamon Press) or Advances in Heterocyclic Chemistry (Academic Press) or Heterocyclic Compounds (Wiley Intersciences).

The subject of the present invention is also the methods of synthesis of the products of formula (IV), in which Z represents a carboxylic ester group, in particular methyl ester, a benzyloxy radical, a hydrogen atom or a hydrogen atom. iodine, a bromine atom, a triflate radical, a boronic acid or ester, a carboxylic acid, a carboxaldehyde or a hydroxyl radical. The products of general formula (IV) in which Z represents a carboxylic ester, a benzyloxy radical, an iodine atom, a bromine atom, a triflate radical, a boronic acid or ester, a carboxylic acid, a carboxaldehyde or a hydroxyl radical may be advantageously prepared in the context of the invention by reacting a product of general formula (II), in which Z represents a carboxylic ester, a benzyloxy radical, an iodine atom or a bromine atom according to the methods general known to those skilled in the art, in particular those described in Comprehensive Organic Chemistry, by D. Barton et al. (Pergamon Press), Advanced Organic Chemistry, by J. March (Wiley Interscience), or Compendium of Organic Synthetic Methods (Wiley Interscience). It is particularly advantageous to use the method described in scheme (8) R'-COOH peptide coupling z = COOMe, OCH2Ph, I, Br H2 z = COOMe, OCH2Ph, I, Br (II) z = COOMe, OCH2Ph, I, Br z = OCH2Ph, I, Br Z = B (OH) Z or B (OR) ZC (O) -OH or C (O) -H) or OTf or 0H B (OR) 2 can form a cycle Diagram (8) Preparation of compounds of general formula (I) Method A from compounds (III): The subject of the present invention is also the methods for synthesizing the products of formula (I), starting from the compounds of general formula ( III) which can be carried out according to the general methods known to those skilled in the art, in particular those described in Comprehensive Organic Chemistry, by D. Barton et al. (Pergamon Press), Advanced Organic Chemistry, by J.March (Wiley Interscience), or Compendium of Organic Synthetic Methods (Wiley Interscience). It is particularly advantageous to use the method of scheme (9): 1) oxime preparation 2) reduction Het R'-COOH Het (I) with R = NH-CO-R 'H and peptide coupling Scheme (9) Method B to From the compounds (IV): The subject of the present invention is also the methods for synthesizing the products of formula (I), starting from the compounds of general formula (IV) which can be carried out according to the general methods known to those skilled in the art. art, particularly those described in Comprehensive Organic Chemistry, by D. Barton et al. (Pergamon Press), Advanced Organic Chemistry, by J.March (Wiley Interscience), or Compendium of Organic Synthetic Methods (Wiley Interscience). When Het does not represent an imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl heterocyl, and is optionally substituted by one or more radicals R1, as defined previously, It is particularly advantageous according to the invention to prepare the compounds of general formula (I) either by coupling of a compound of general formula (IV) in which z represents an iodine atom, a bromine atom or the trifluoromethanesulfonyloxy radical. with a boronic heterocyclic derivative, acid or ester, or by coupling of a compound of general formula (IV) in which z represents a boronic acid or a boronic ester, optionally cyclic - such as the methyl ester of n-butyl , isopropyl or pinacole with a bromo or iodo heterocycle, under the conditions of the Suzuki reaction, in the presence of a palladium derivative (0) as a catalyst, according to scheme (10): (IV) Z = I, Br, OTf (I) ( IV) Z = B- (OH) 2, B (Oalk) 2 Scheme (10) More particularly, when the heterocycle Het is of the benzimidazole or azabenzimidazole type or else of the benzoxazole or azabenzoxazole, benzothiazole or azabenzothiazole type, bound by its position 2 at the 5-position of pyrrolo [1,2-a] indole, it is particularly advantageous to form said heterocycle by coupling of an orthophenylenediamine or diamino-pyridine derivative or ortho-aminophenol derivative, orthoaminothiophenol or amino-hydroxy-pyridine or ortho-disubstituted amino-mercapto-pyridine - with an acid, an acid chloride, a methyl ester, or a carboxaldehyde in position 5 of the pyrrolo [1,2 -a] indole according to scheme (11): OH (alk), B4OH (alk) 1 Het Het Br (1) Het -t "Pd (O)" "Pd (0) 36 R1 ~ / AH V1 NH2 1) coupling 2) cyclization A = NH2O, S

Z = COOH, COOMe, CHO V1 = N, CRI R1 as defined above

Scheme (II) When the 5-carboxylic acid derivative of pyrrolo [1,2-a] indole is used, it is particularly advantageous to activate this acid using a coupling agent known to the person skilled in the art. the art, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in the presence of 1-hydroxybenzotriazole (HOBT), o - ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N tetrafluoroborate N, N'-tetramethyluronium (TOTU) or o- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU).

When a methyl ester derivative of 5-carboxylic acid of pyrrolo [1,2-a] indole is used, it is advantageous in the context of the invention to operate in the presence of trimethylaluminium in a halogenated organic solvent. , such as dichloromethane or dichloroethane.

When a 5-carboxaldehyde derivative of pyrrolo [1,2-a] indole is used, it is advantageous, in the context of the invention, to operate:

or by microwave heating in the presence of silica, according to Tetrahedron Lett. 1998, 39, 4481-84; or in the presence of dichloro-dicyano-benzoquinone (DDQ), according to Tetrahedron 1995, 51, 5813-18;

or in the presence of a mixture of thionyl chloride and pyridine, according to E.P. 511187;

- in the presence of ferric chloride, according to Eur. J. Med. Chem. 2006, 31, 635-42. Various cyclization conditions of the mixture of intermediate amides can be used in the context of the invention, such as acetic acid or a mixture of trifluoroacetic acid and anhydride. It is also particularly advantageous, in the context of the invention, to carry out this type of thermal cyclization in an acid medium by heating in a microwave reactor.

More particularly, when said heterocycle is of imidazole, oxazole, or thiazole type, linked by its 2-position to the 5-position of pyrrolo [1,2-a] indole, it is particularly advantageous to form said heterocycle from an acid. , an ester or an aldehyde at the 5-position of pyrrolo [1,2-a] indole, according to scheme (12): 1) coupling 2) NH 2 (IV) cyclization A = NH 2 O, SB = AH or a precursor reactive group of A z = COOH, COOMe, CHO Scheme (12)

In the context of the invention, it is particularly advantageous to operate:

4. in the case where said heterocycle is an imidazole or an imidazoline:

- from a 2-azidoethylamine, according to Tetrahedron, 47 (38),

1991, 8177-94, - an ethylenediamine, according to Biorg. Med. Chem Lett. 12 (3), 2002, 471-75,

glyoxal and ammonia, according to J. Med. Chem., 46 (25), 2003, 5416-27;

5. in the case where said heterocycle is an oxazole or an oxazoline: from a 2-azidoethanol, according to J. Org. Chem., 61 (7), 1996, 2487-96, B optionally isolated (I) 3) C 38 - oxidation of a 2-aminoethanol, according to J. Med. Chem. 47 (8), 2004, 1969-86 or Khim. Geterosiki. Soed. 1984 (7), 881-4, 2-aminoacetaldehyde diethyl acetal, according to Heterocycles, 39 (2), 1994, 767-78; 6. in the case where said heterocycle is thiazole or a thiazoline: - from a 2-chloro-ethylamine and Lawesson's reagent, according to Helv. Chim. Acta, 88 (2), 2005, 187-95, 2-aminoethanethiol, according to J. Org. Chem. 69 (3), 2004, 811-4, or Tetrahedron Let, 41 (18), 2000, 3381-4. More generally, it is advantageous in the context of the invention to form the heterocycle a product of general formula (IV) from a triflate, a brominated or iodinated derivative, a boronic acid or ester, a carboxylic acid or a carboxylic acid ester or an aldehyde, in position 5 of pyrrolo [1,2-a] indole by any of the synthetic methods known to those skilled in the art, such as those described in Comprehensive Organic Chemistry, by DHR Barton et al. (Pergamon Press) or Advances in Heterocyclic Chemistry (Academic Press) or Heterocyclic Compounds (Wiley Intersciences).

The subject of the present invention is therefore also, as new industrial products, the synthetic intermediates of formulas (II), (III) and (IV): (II) (III) H and Z = OTf, I, Br, B (OH) 2 or B (OR) 2 * or C (O) -OMe, C (O) -OH or C (O) -H) or OH or O-CHZ Ph * B (OR) 2 which can form a ring

compounds of formulas (II), (III) and (IV) as defined above in which the substituents Het and R have the meanings indicated above for the products of formula (I) and za the meaning indicated above except for the compound of formula (II) wherein z represents an iodine atom. The products of the present invention are endowed with valuable pharmacological properties: they have been found to possess, in particular, properties inhibiting the activities of chaperone proteins and in particular their ATPase activities.

Among these chaperones proteins, mention is made in particular of the human chaperone HSP90.

The products corresponding to the general formula (I) as defined above thus have a significant Hsp90 chaperone inhibitory activity. Tests given in the experimental section below illustrate the inhibitory activity of products of the present invention with respect to such chaperone proteins. These properties therefore make the products of general formula (I) of the present invention usable as medicaments for the treatment of malignant tumors. The products of formula (I) may also be used in the veterinary field. The subject of the invention is therefore the application, as medicaments, of the products of formula (I) as defined above.

The subject of the invention is particularly the application as medicaments of the products of formula (I) as defined above whose names follow: [5- (6-fluoro-1H-benzimidazol-2- 1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid (1H) -9H-pyrrolo [1,2-a] indol-9-yl] amide. 1H-10-pyrrolo [2,3-b] pyridine-4-carboxylic acid (5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-yl) -amide. [1- (3H-Imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide of 1H-pyrrolo acid [2,3-b] pyridine-4-carboxylic acid. 6-chloro-1-acid [5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide H-pyrrolo [2,3-b] pyridine-4-carboxylic acid. As well as the addition salts with the inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

The subject of the invention is, in particular, as medicaments, products of formula (I) as defined above: Het is chosen from the group consisting of: R'1 1 NN H R1 with: R1 represents H, F, Cl, Br, CF3, NO2, CN, CH3, OH, OCH3, OCF3, CO2Me, CONH2, CONHMe, CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC ( 0) Me, SO2NH2, SO2N (Me) 2, R'1 represents H, CONH2, CONHMe and OMe, R "1 represents F, Cl, OH, OMe, CN, O- (CH2) 3-OMe and O- (CH2) 3-N (Me) 2 and R is selected from the group consisting of: NH NH NH NH NH NH NH → NH-NH NH NH NH N → N and their prodrugs formula (I) being in all the possible tautomeric, racemic, enantiomeric and diastereoisomeric isomeric forms, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I) The products can be administered parenterally, orally, perlingually The invention also relates to pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs of general formula (I).

These compositions may be presented in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, creams, ointments and lotions. These pharmaceutical forms are prepared according to the usual methods. The active ingredient may be incorporated into excipients usually used in these compositions, such as aqueous vehicles or not, talc, gum arabic, lactose, starch, magnesium stearate, animal fats or vegetable, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The usual dose, variable depending on the subject treated and the condition in question, may be, for example, 10 mg to 1 g per day in humans, orally.

The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments intended to inhibit the activity of chaperone proteins and especially of Hsp90 .

The present invention thus relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the chaperone protein is HSP90.

The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent or treat a disease characterized by the disruption of the activity of a chaperone protein Hsp90 type and in particular such a disease in a mammal. The present invention relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said 43 products of formula (I) for the preparation of a medicament for preventing or treating a disease belonging to the next group: neurodegenerative diseases such as Huntington's disease, Parkinson's disease, focal cerebral ischemia, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis, malaria, Brugia and Bancroft filariasis , toxoplasmosis, treatment-resistant fungi, hepatitis B, hepatitis C, herpes virus, dengue (or tropical flu), spinal and bulbar muscular atrophy, mesangial cell proliferation disorders , thromboses, retinopathies, psoriasis, muscular degeneration, diseases in oncology, cancers.

The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating diseases in oncology.

The present invention particularly relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating cancers.

Among these cancers, the present invention is particularly interested in the treatment of solid tumors and in the treatment of cancers resistant to cytotoxic agents.

The present invention thus relates in particular to the use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to treat cancers including lung, breast and ovarian cancers, glioblastomas, chronic myeloid leukemias, acute lymphoblastic leukemias, prostate, pancreatic and colon cancers, metastatic melanomas, tumors of the thyroid and renal carcinoma. Among the main potential indications of Hsp90 inhibitors, there may be mentioned, without limitation:

- non-small cell lung cancers, breast cancers, ovarian cancers and glioblastomas that overexpress EGF-R or HER2; chronic myeloid leukemias which overexpress Bcr-Abl;

acute lymphoblastic leukaemias which overexpress Flt-3;

- Breast, prostate, lung, pancreatic, colon or ovarian cancers that overexpress Akt;

metastatic melanomas and thyroid tumors which overexpress the mutated form of the B-Raf protein;

- androgen-dependent and androgen-independent prostate cancers;

estrogen-dependent and estrogen-independent breast cancers;

renal carcinomas that overexpress HIF-1a or the mutated c-met protein.

The present invention is more particularly concerned with the treatment of breast, colon and lung cancer.

The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended for the chemotherapy of cancers.

As medicaments according to the present invention intended for the chemotherapy of cancers, the products of formula (I) according to the present invention may be used alone or in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents. The present invention thus relates in particular to pharmaceutical compositions as defined above additionally containing active principles of other cancer chemotherapy drugs.

Such therapeutic agents may be commonly used anti-tumor agents.

Examples of known inhibitors of protein kinases include butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomucine, Glivec and Iressa.

The products of formula (I) according to the present invention can thus also advantageously be used in combination with anti-proliferative agents: by way of examples of such anti-proliferative agents but without however being limited to this list, mention may be made of aromatase inhibitors, antiestrogens, topoisomerase inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, inhibitors MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, proteasome inhibitors, histone deacylase inhibitors (HDACs), and especially HDAC6 inhibitors, compounds that decrease the activity of protein kinases. and also antiangiogenic compounds, gonadorelin agonists, antiandrogens, and

The present invention thus relates to products of formula (I) as Hsp90 chaperone inhibitors, said products of formula (I) being in all possible isomeric forms tautomers, racemic, enantiomers and diastereoisomers, as well as salts of addition with the inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I) as well as their prodrugs.

The present invention particularly relates to products of formula (I) as defined above as HSP90 inhibitors. The products of formula (I) according to the present invention can be prepared by the application or the adaptation of known methods and in particular methods described in the literature such as those described by RCLarock in: Comprehensive Organic Transformations, VCH publishers , 1989.

In the reactions described below, it may be necessary to protect reactive functional groups such as for example hydroxy, amino, imino, thio or carboxy groups, when these are desired in the final product but when their participation does not occur. is not desired in the synthesis reactions of the products of formula (I). Conventional protecting groups may be used in accordance with standard standard practices such as those described for example by TW Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

The following experimental part gives non-limiting examples of starting materials: other starting materials can be found commercially or prepared according to the usual methods known to those skilled in the art. Examples Illustrating the Invention The examples whose preparation follows illustrate the present invention without however limiting it.

All the examples described have been characterized by proton NMR spectroscopy and mass spectroscopy, the majority of these examples have also been characterized in infrared spectroscopy. Unless otherwise specifically described, the LC / MS mass spectra, reported in the description of the various examples below, were carried out under the following liquid chromatographic conditions: Method A: The spectra were obtained on a Waters apparatus ZQ Ionisation: electrospray in positive and / or negative (ES +/-) mode 47 Chromatographic conditions: - Column: XBridge C18 2.5 μm 3 x 50 mm - Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid) - Column temperature: 70 ° C - Flow rate: 0.9 ml / min - Gradient (7 min): from 5 to 100% of B in 5.3 min; 5.5 min: 100% B; 6.3 min: 5% of B Method B: The spectra were obtained on a WATERS QUATTRO FIRST Ionisation apparatus: electrospray in positive and / or negative mode (ES +/-) Chromatographic conditions: - Column: ACQUITY BEH C18 1,7 pm - 2.1 x 50 mm - Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid) - Column temperature: 70 ° C - Flow rate: 0.7 ml / min Gradient (3.7 min): from 5 to 100% of B in 3 min; 3.6 min: 5% of B Method C: The spectra were obtained on a WATERS QUATTRO FIRST Ionisation apparatus: electrospray in positive and / or negative mode (ES +/-) Chromatographic conditions: - Column: ACQUITY BEH C181.7 pm - 2.1 x 50 mm - Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid) - Column temperature: 70 ° C - Flow rate: 0.7 ml / min - Gradient (6 min): from 5 to 100% of B in 5 min; 5.5 min: 5% of B 48 Method D: The spectra were obtained on a WATERS UPLC-SQD apparatus Ionisation: electrospray in positive and / or negative mode (ES +/-) Chromatographic conditions: - Column: ACQUITY BEH C18 1 , 7 pm - 2.1 x 50 mm - Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid) - Column temperature: 50 ° C - Flow rate: 1 ml / min Gradient (2 min): from 5 to 50% of B in 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% of B Example 1: Synthesis of [5- (6-fluoro-1H-benzimidazol-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] amide acid 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid. Step 1: Method 1: In an autoclave, a mixture of 1.000 g of 5-iodo-pyrrolo [1,2-a] indol-9- is maintained for 16 hours at 50 ° C. under 2 bar of carbon monoxide pressure. one (which may be prepared according to J. Med., 2004, 47 (6), 1448), 152 mg of palladium acetate and 280 mg of 1,3-diphenylphosphinopropane and 0.47 mL of triethylamine in 6 mL of methanol and 15mL of dimethylformamide. After purging with argon, the reaction medium is filtered by washing the insoluble material with methanol and then evaporating the filtrate to dryness. The orange-brown residue is chromatographed on silica gel (40-63pm) eluting with dichloromethane. 800 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid methyl ester are obtained in the form of a beige solid whose characteristics are as follows: NH 49 - Spectrum of 1H NMR (400MHz, 8 ppm, DMSO-d6): 3.95 (s, 3H); 6.43 (dd, J = 3.8 and 2.7 Hz, 1H); 6.98 (dd, J = 3.8 and 1.0 Hz, 1H); 7.33 (t, J = 7.5 Hz, 1H); 7.78 (dd, J = 7.5 and 1.4 Hz, 1H); 7.97 to 8.03 (m, 2H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 3.48; [Method 2] In a 50mL flask was added at room temperature 3mL of a 1M solution of boron tribromide in dichloromethane to a mixture of 260mg of dimethyl ester of methylene chloride. 2-pyrrol-1-yl-isophthalic acid (which may be prepared according to Helvetica Chim.Acta 1983, 66 (7), 2135) dissolved in 4 mL of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours and then 5 ml of water are added. After decantation, the aqueous phase is re-extracted with twice 15 ml of dichloromethane. The combined organic phases are washed with twice 20 ml of water, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40pm) eluting with a mixture of dichloromethane and cyclohexane (50/50 v / v). 122 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid methyl ester are obtained in the form of a yellowish solid whose characteristics are identical to those of the product obtained by the Method 1. Step 2: In a 250 ml flask, a mixture of 800 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-methyl ester was refluxed for 3 hours. carboxylic acid obtained according to the preceding step and 740 mg of lithium hydroxide monohydrate in 25 ml of water and 100 ml of methanol. The reaction medium is evaporated to dryness under vacuum, the solid residue is taken up in 35 ml of water and brought to pH 3 with 5M hydrochloric acid. A precipitate appears and the medium is extracted with 3 times 35 ml of a mixture of dichloromethane and methanol (95/5 v / v). the combined organic extracts are washed with 3 times 15 ml of water, dried over magnesium sulphate and evaporated to dryness under vacuum. 630 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid are obtained in the form of a beige solid whose characteristics are the following: 50 2932484 - Mass spectrum (LC / MS Method A): Retention time Tr (min) = 2.69; [M + H] +: m / z 214; [MH] -: m / z 212. Step 3: In a 250 ml flask under argon, a mixture of 620 mg of 9-oxo-9H-pyrrolo [1,2-a] acid is stirred at room temperature for 1 hour. indole-5-carboxylic acid obtained according to the preceding step, of 1.50 g of o- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) and 0.44 ml of diisopropylethylamine in 55mL of tetrahydrofuran. 367 mg of 4-fluoro-optenylenediamine are then added and stirring is continued for 3 days. The reaction medium is evaporated to dryness in vacuo and the residue is taken up in 15 ml of a mixture of dichloromethane and methanol (90/10 v / v). The organic phase is washed with 10 ml of a saturated solution of sodium bicarbonate and then with 3 times 5 ml of distilled water and dried over magnesium sulphate. After evaporation to dryness under vacuum, the residue is deposited in dry spot on a column of silica gel (40-63pm) and chromatographed eluting with a mixture of dichloromethane and methanol (95/5 v / v). 379 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid (2-amino-4-fluoro-phenyl) -amide are obtained in the form of a beige solid whose Characteristics are as follows: 1 H NMR spectrum (400 MHz, 8 ppm, DMSO-d6): 5.38 (bs, 2H); 6.35 (dd, J = 3.5 and 2.5 Hz, 1H); 6.39 (td, J = 8.6 and 2.9 Hz, 1H); 6.55 (dd, J = 11.2 and 2.9 Hz, 1H); 6.92 (broad d, J = 3.5 Hz, 1H); 7.22 (dd, J = 8.6 and 6.4 Hz, 1H); 7.33 (t, J = 7.6 Hz, 1H); 7.57 (broad d, J = 2.5 Hz, 1H); 7.68 (broad d, J = 7.6 Hz, 1H); 7.94 (broad d, J = 7.6 Hz, 1H); 9.91 (s, 1H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 3.10; [M + H] +: m / z 322; [MH] -: m / z 320. Step 4: In a 250 ml flask, refluxing for 3 hours a mixture of 375 mg of 9-oxo acid (2-amino-4-fluoro-phenyl) -amide. -9H-pyrrolo [1,2-a] indole-5-carboxylic acid obtained according to the previous step in 40mL of glacial acetic acid. The reaction medium is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (15-40pm) eluting with a gradient of methanol (0% to 30% by volume) in dichloromethane. 119 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -pyrrolo [1,2-a] indol-9-one are obtained in the form of a yellowish solid, the characteristics of which are as follows: Spectrum 1H NMR (400MHz, 8 ppm, DMSO-d6): 6.36 (dd, J = 3.9 and 2.9Hz, 1H); 6.96 (dd, J = 3.9 and 1.0 Hz, 1H); 7.16 (td, J = 9.5 and 2.4 Hz, 1H); 7.42 (t, J = 7.6 Hz, 1H); 7.50 (broad d, J = 9.5 Hz, 1H); 7.69 (dd, J = 7.6 and 1.0 Hz, 1H); 7.72 (partially masked m, 1H); 7.99 (dd, J = 7.6 and 1.0 Hz, 1H); 8.45 (dd, J = 2.9 and 1.0 Hz, 1H); 13.30 (spread m, 1H). Mass Spectrum (LC / MS Method B): Retention Time Tr (min) = 1.83; [M + H] +: m / z 304; [MH] -: m / z 302. Step 5: In a 20 ml flask, a mixture of 60 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -pyrrolo [1,2-a] is refluxed. ] Indol-9-one obtained according to the preceding step and 42 mg of hydroxylamine hydrochloride in 5 ml of pyridine for 6 hours. The reaction medium is evaporated to dryness under vacuum and the residue taken up with 25 ml of a saturated solution of sodium bicarbonate is extracted with 3 times 25 ml of ethyl acetate. The combined organic phases are washed with 25 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. 97 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -pyrrolo [1,2-a] indol-9-one oxime are obtained in the form of a yellowish oil, the characteristics of which are as follows: 1H NMR Spectrum (400MHz, 8 ppm, DMSO-d6): 6.34 (dd, J = 3.4 and 2.9Hz, 1H); 6.78 (dd, J = 3.4 and 1.0 Hz, 1H); 7.14 (td, J = 10.5 and 3.0 Hz, 1H) 7.37 (t, J = 7.7 Hz, 1H); 7.48 (spread m, 1H); 7.68 (spread m, 1H); 7.82 (d, J = 7.7 Hz, 2H); 8.10 (broad d, J = 2.9 Hz, 1H); 12.14 (s, 1H); 13.2 (spread m, 1H) for the majority E or Z isomer. Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 3.65; [M + H] +: m / z 319; [M-H] -: m / z 317.

Step 6: 90 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -pyrrolo [1,2-a] indol-9-one oxime 52 obtained according to US Pat. previous step in a mixture of 2 ml of acetic acid, 2 ml of ethanol and 2 ml of water. 19 mg of zinc are added to the powder and stirring is maintained for 30 minutes. The reaction medium is filtered on clarcel, washed with 80 ml of methanol and the filtrate is evaporated to dryness in vacuo. The residue is chromatographed on silica gel (15-40pm) eluting with a mixture of methanol and dichloromethane (5/95 v / v). 42 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -9H-pyrrolo [1,2-a] indol-9-ylamine acetate are obtained in the form of a beige solid whose characteristics are the following: 1 H NMR spectrum (400MHz, 8 ppm, DMSO-d6): 1.89 (s, 3H); 4.93 (s, 1H); 6.08 to 6.20 (m, 2H); 7.12 (t broad, J = 9.5 Hz, 1H); 7.24 to 7.80 (very spread m, 2H); 7.29 (t, J = 7.8 Hz, 1H); 7.53 (brs, 1H); 7.64 (broad d, J = 7.8 Hz, 1H); 7.71 (broad d, J = 7.8 Hz, 1H); 13.08 (spread m, 1H). Mass spectrum (LC / MS Method A): Retention time Tr (min) = 2.51; [M + H] +: m / z 305; [M + H-NH 3] +: m / z 288 (base peak); [M-H] -: m / z 303.

Step 7: A mixture of 42 mg of 5- (6-fluoro-1H-benzimidazol-2-yl) -9H-pyrrolo [1,2-a] indol-9-ylamine acetate is stirred in a 100 ml flask. according to the preceding step, 19 mg of 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid (which may be obtained according to WO 2003/000688), 39 mg of o - ((ethoxycarbonyl) tetrafluoroborate ) cyanomethyleneamino) -N, N, N ', N'-tetramethyluronium (TOTU) and 16 μl of diisopropylethylamine in 3 ml of N-methylpyrrolidone. After 1 hour the reaction medium is evaporated to dryness, the residue is taken up with 30 ml of a saturated solution of sodium bicarbonate and the aqueous phase is extracted with 4 times 30 ml of ethyl acetate. The combined organic phases are washed with 3 times 30 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40pm) eluting with a gradient of methanol (2% to 5% v / v) in dichloromethane then on a second column of silica gel (15-40pm) eluting with pure ethyl acetate. 12 mg of [5 - (6-fluoro-1H-benzimidazol-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] amide of 1H-pyrrolo [2] acid are obtained; 3-b] pyridine-4-carboxylic acid in the form of a brown solid, the characteristics of which are as follows: 1 H NMR spectrum: (400 MHz, 8 ppm, DMSO-d 6): 6.22 to 6.28 (m, 2H); 6.40 (d, J = 7.8 Hz, 1H); 6.89 (dd, J = 3.4 and 2.0 Hz, 1H); 7.13 (spread m, 1H); 7.33 (t, J = 7.6 Hz, 1H); 7.38 (spread m, 1H); 7.44 (d, J = 4.9 Hz, 1H); 7.52 to 7.83 (m, 5H); 8.28 (d, J = 4.9 Hz, 1H); 9.30 (d, J = 7.8 Hz, 1H); 11.85 (br m, 1H); 13.14 (s, 1H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 3.53; [M + H] +: m / z 449; [2M + H] +: m / z 897; [M + 2H + CH 3 CN] 2+: m / z 245.5 (peak of 10 base).

Example 2 Synthesis of 1H-pyrrolo [2,3-b] pyridine-4-di (5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-yl) -amide carboxylic acid. Step 1: In a 100 ml flask under argon, a mixture of 361 mg of 5-iodo-pyrrolo [1,2-a] indol-9-one (which may be prepared according to J.) is heated to 123 ° C. Med.Chem. 2004, 47 (6), 1448), 214mg of 3-quinoline boronic acid, 603mg of cesium carbonate and 143mg of tetrakis (triphenylphosphine) palladium (0) in 20mL of dimethylformamide. After 3 hours, the reaction medium is evaporated to dryness under vacuum and the residue taken up in ethyl acetate is filtered. The filtrate is washed with water, twice with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried with magnesium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (15-40pm) eluting with a gradient of ethyl acetate (20% to 30% v / v) in n-heptane. 231 mg of 5-quinolin-3-yl-pyrrolo [1,2-a] indol-9-one are obtained in the form of a solid whose characteristics are the following: 1 H NMR spectrum: (400 MHz, 8 ppm) , CDCl3): 6.08 (dd, J = 3.8 and 2.6 Hz, 1H); 6.33 (dd, J = 2.6 and 0.9 Hz, 1H); 6.80 (dd, J = 3.8 and 0.9 Hz, 1H); 7.27 (t, J = 7.7 Hz, 1H); 7.41 (dd, J = 7.7 and 1.3 Hz, 1H); 7.65 to 7.72 (m, 2H); 7.85 (m, 1H); 7.92 (broad d, J = 8.3 Hz, 1H); 8.24 (broad d, J = 8.3 Hz, 1H); 8.32 (d, J = 2.2 Hz, 1H); 9.07 (d, J = 2.2 Hz, 1H). Step 2: In a 100 ml flask, a mixture of 231 mg of 5-quinolin-3-yl-pyrrolo [1,2-a] indol-9-one obtained according to the preceding step and 164 mg of hydroxylamine hydrochloride in 20mL of pyridine. After 1.5 hours of heating, the reaction medium is evaporated to dryness in vacuo. The residue is taken up in saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (15-40pm) eluting with a gradient of methanol (2% to 3% v / v) in dichloromethane. 277 mg of 5-quinolin-3-yl-pyrrolo [1,2-a] indol-9-one oxime hydrochloride are obtained in the form of a yellowish solid whose characteristics are the following: 1 H NMR spectrum: (400 MHz) 8 ppm, DMSO-d 6): 6.20 (dd, J = 3.5 and 2.9 Hz, 1H); 6.24 (dd, J = 2.9 and 1.1 Hz, 1H); 6.72 (dd, J = 3.5 and 1.1 Hz, 1H); 7.34 (t, J = 7.7 Hz, 1H); 7.47 (dd, J = 7.7 and 1.3 Hz, 1H); 7.72 (m, 1H); 7.78 (dd, J = 7.7 and 1.3 Hz, 1H); 7.88 (m, 1H); 8.10 (broad d, J = 7.9 Hz, 1H); 8.15 (broad d, J = 7.9 Hz, 1H); 8.62 (d, J = 2.2 Hz, 1H); 9.06 (d, J = 2.2 Hz, 1H); 12.18 (spread m, 1H) for the predominant E or Z isomer. Step 3: In a 100 ml flask a mixture of 277 mg of 5-quinolin-3-yl-pyrrolo [1,2-a] indol-9-one oxime hydrochloride obtained according to the previous step in 5 ml is stirred at room temperature. acetic acid, 5 ml of ethanol and 5 ml of water. 58 mg of powdered zinc are added and the mixture is stirred for 1.5 hours. Another 58mg of powdered zinc is added and stirred for 3.5 hours. The reaction medium is clarcel filtered washing with 100 ml of methanol. The filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (15-40pm) eluting with a gradient of methanol (2% to 7% v / v) in dichloromethane. 116 mg of 5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-ylamine acetate are obtained in the form of a brown solid whose characteristics are the following: 1 H NMR spectrum: (300MHz, 6 ppm, DMSO-d6): 1.89 (s, 3H); 4.96 (s, 1H); 5.98 (broad d, J = 3.1 Hz, 1H); 6.05 (t, J = 3.1 Hz, 1H); 6.14 (dt, J = 3.1 and 1.2 Hz, 1H); 7.28 (t, J = 7.5 Hz, 1H); 7.35 (dd, J = 7.5 and 1.2 Hz, 1H); 7.65 to 7.74 (m, 2H); 7.86 (m, 1H); 8.09 (broad d, J = 8.0 Hz, 1H); 8.14 (broad d, J = 8.0 Hz, 1H); 8.53 (d, J = 2.3 Hz, 1H); 9.00 (d, J = 2.3 Hz, 1H). Step 4: In a 100 ml flask under argon, a mixture of 116 mg of 5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-ylamine acetate is stirred at room temperature for 18 hours. obtained according to the preceding step, 63 mg of 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid (which may be obtained according to WO 2003/000688), 82 mg of N- (3) hydrochloride. -dimethylaminopropyl) -N'-ethylcarbodiimide (EDCI) and 58mg of 1-hydroxybenzotriazole (HOBt) in 7.5mL of dimethylformamide. The reaction medium is evaporated to dryness under vacuum and the residue is added with 50 ml of water and the suspension is stirred for 1 hour. The solid is filtered and washed with water, then a saturated solution of sodium bicarbonate and again with water. It is filtered off overnight and then the solid is taken up in a mixture of methanol and dichloromethane (10/90 v / v) and the solvent is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40pm) eluting with a mixture of methanol and dichloromethane (3/97 v / v). 53 mg of 1H-pyrrolo [2,3-b] pyridine-4- (5-quinolin-3-yl-9H-pyrrolo [1,2-a] indol-9-yl) -amide are obtained. carboxylic acid in the form of a beige solid, the characteristics of which are as follows: 1 H NMR spectrum: (300 MHz, 6 ppm, DMSO-d 6): 6.09 (broad d, J = 3.2 Hz, 1H); 6.13 (t, J = 3.2 Hz, 1H); 6.24 (dm, J = 3.2 Hz, 1H); 6.44 (broad d, J = 8.3 Hz, 1H); 6.90 (broad d, J = 3.3 Hz, 1H); 7.32 (t, J = 7.7 Hz, 1H); 7.41 to 7.47 (m, 56H); 7.60 to 7.67 (m, 2H); 7.73 (m, 1H); 7.88 (m, 1H); 8.10 to 8.18 (m, 2H); 8.29 (d, J = 5.0 Hz, 1H); 8.57 (spread m, 1H); 9.04 (broad m, 1H); 9.33 (d, J = 8.3 Hz, 1H); 11.89 (spread m, 1H). Mass Spectrum (LC / MS Method C): Retention Time Tr (min) = 2.36; [M + H] +: m / z 442; [M-H] -: m / z 440.

Example 3 Synthesis of [5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide acid [1] H-pyrrolo [2,3-b] pyridine-4-carboxylic acid. 1

Step 1: In a 500 ml flask a mixture of 730 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid obtained according to step 2 is stirred for 19 hours at room temperature. of Example 1, 373 mg of 3,4-diaminopyridine, 721 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) and 508 mg of 1-hydroxybenzotriazole (HOBt) in 60 ml of dimethylformamide. . The reaction medium is evaporated to dryness under vacuum and the solid residue is taken up in 50 ml of water. The precipitate is filtered and the solid is washed successively with 3 times 80 ml of water, 3 times 80 ml of a saturated solution of sodium bicarbonate and again with 3 times 80 ml of water. The solid is dissolved in methanol and the solvent evaporated to dryness in vacuo. The residue is chromatographed on silica gel (15-40pm) eluting with a gradient of methanol (5% to 10% v / v) in dichloromethane and then a mixture of dichloromethane and 5N ammonia methanol (90/10 v / v ). 220 mg of 9-oxo-9H-pyrrolo [1,2-a] indole-5-carboxylic acid (4-amino-pyridin-3-yl) -amide are obtained in the form of a solid whose characteristics are as follows: 1H NMR spectrum: (400MHz, 8 ppm, DMSO-d6): 6.02 (bs, 2H); 6.35 (dd, J = 3.7 and 2.7 Hz, 1H); 6.66 (d, J = 5.6 Hz, 1H); 6.92 (dd, J = 3.7 and 1.15 Hz, 1H); 7.33 (t, J = 7.7 Hz, 1H); 7.58 (dd, J = 2.7 and 1.1 Hz, 1H); 7.68 (dd, J = 7.7 and 1.3 Hz, 1H); 7.95 (d, J = 5.6 Hz, 1H); 8.00 (dd, J = 7.7 and 1.3 Hz, 1H); 8.15 (s, 1H); 10.00 (s wide, 1H). Step 2: In a 20 ml microwave reactor, a mixture of 256 mg of 9-oxo-9H-pyrrolo acid (4-aminopyridin-3-yl) -amide is heated at 200 ° C. for 30 minutes. [1,2-a] indole-5-carboxylic acid obtained according to the preceding step in 20 ml of glacial acetic acid. The reaction medium is filtered clarcel by washing with glacial acetic acid. The filtrate is evaporated to dryness under vacuum and the residue is taken up twice with toluene and reevaporated each time to dryness in vacuo. The solid is triturated in isopropyl ether, filtered and dried under vacuum at 40 ° C for 1 night. 111 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolo [1,2-a] indol-9-one are obtained in the form of a solid whose characteristics are as follows: 1H NMR spectrum: (400MHz, 8 ppm, DMSO-d6): 6.38 (dd, J = 3.9 and 2.6Hz, 1H); 6.98 (dd, J = 3.9 and 1.1 Hz, 1H); 7.43 (t, J = 7.6 Hz, 1H); 7.72 (dd, J = 7.6 and 1.4 Hz, 1H); 7.76 (broad d, J = 5.6 Hz, 1H); 8.11 (broad d, J = 7.6 Hz, 1H); 8.38 (d, J = 5.6 Hz, 1H); 8.50 (spread m, 1H); 9.11 (s large, 1H); 13.8 (m very spread, 1H). Step 3: In a 250 ml flask under argon, a mixture of 444 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolo [1,2-a] was refluxed for 3 hours. indol-9-one obtained according to the preceding step and 323 mg of hydroxylamine hydrochloride in 60 ml of pyridine. The reaction medium is evaporated to dryness in vacuo and the residue is taken up in saturated sodium bicarbonate solution and the precipitate is filtered off and washed with water. The solid is dissolved in methanol and the solvent evaporated to dryness in vacuo. The residue is taken up in toluene and then evaporated to dryness in vacuo. 380 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolo [1,2-a] indol-9-one oxime are obtained in the form of a solid, the characteristics of which are as follows: 1H NMR Spectrum: (400MHz, 8 ppm, DMSO-d6): 6.25 (dd, J = 3.5 and 2.9 Hz, 1H); 6.72 (dd, J = 3.5 and 1.3 Hz, 1H); 7.18 (t, J = 7.7 Hz, 1H); 7.34 (dd, J = 5.5 and 1.2 Hz, 1H); 7.59 (dd, J = 7.7 and 1.4 Hz, 1H); 7.86 (d, J = 5.5 Hz, 1H); 58 .29 (dd, J = 7.7 and 1.4 Hz, 1H); 8.69 (d, J = 1.2 Hz, 1H); 9.23 (dd, J = 2.9 and 1.3 Hz, 1H) for the predominant E or Z isomer. Step 4: In a 100 ml flask, a mixture of 200 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -pyrrolo [1,2-enclot-9-one] is stirred at room temperature. oxime obtained according to the preceding step in 5 ml of glacial acetic acid, 5 ml of ethanol and 5 ml of water. 43mg of powdered zinc are added and stirring is maintained at room temperature for 2 hours. The reaction medium is clarcel filtered with washing with methanol. The filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (15-40pm) eluting with a mixture of dichloromethane and 5N ammoniaal methanol (95/5 v / v). 51 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-ylamine are obtained in the form of a solid whose characteristics are the following: 1 H NMR spectrum: (400MHz, 3 ppm, DMSO-d6): 4.94 (s, 1H); 6.14 to 6.20 (m, 2H); 7.31 (t, J = 7.6 Hz, 1H); 7.54 (brs, 1H); 7.64 (d, J = 5.6 Hz, 1H); 7.70 (d, J = 7.6 Hz, 1H); 7.74 (d, J = 7.6 Hz, 1H); 8.36 (d, J = 5.6 Hz, 1H); 9.01 (s, 1H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 0.32; [M + H] +: m / z 288; [M + H-N H3] +: m / z 271; [M-H] -: m / z 286.

Step 5: In a 100 ml flask, a mixture of 51 mg of 5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1, is stirred for 4 hours under argon at room temperature. 2-a] indol-9-ylamine obtained according to the preceding step, of 28 mg of 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid (which may be obtained according to WO 2003/000688), 37 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) and 26 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide. The reaction medium is evaporated to dryness under vacuum. The residue is triturated in 20 ml of water and then filtered. The solid is washed with a saturated solution of sodium bicarbonate, taken up in a mixture of dichloromethane and methanol and the solution is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40pm) eluting with a mixture of dichloromethane and methanol (98/2 v / v). 47 mg of [5 - (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide of 1 H-acid are obtained. pyrrolo [2,3-b] pyridine-4-carboxylic acid in the form of a solid whose characteristics are the following: 1 H NMR spectrum: (400 MHz, 8 ppm, DMSO-d 6): 6.22 to 6.28 (m, 2H); 6.40 (d, J = 8.2 Hz, 1H); 6.89 (dd, J = 3.4 and 2.0 Hz, 1H); 7.33 (t, J = 7.7 Hz, 1H); 7.44 (d, J = 5.1 Hz, 1H); 7.61 (dd, J = 3.4 and 2.5 Hz, 1H); 7.64 (d, J = 6.2 Hz, 1H); 7.67 (broad d, J = 7.7 Hz, 1H); 7.84 (d, J = 7.7 Hz, 1H); 7.85 (spread m, 1H); 8.28 (d, J = 5.1 Hz, 1H); 8.33 (d, J = 6.2 Hz, 1H); 9.01 (s, 1H); 9.29 (d, J = 8.2 Hz, 1H); 11.84 (br m, 1H); 13.47 (spread m, 1H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 2.39; [M + H] +: m / z 432; [M-H] -: m / z 430.

Example 4 Synthesis of [5- (3H-Imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-15 a] indol-9-yl] -amide of Acid 6 1-chloro-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid. Step 1: In a tricolor of 100 ml, a solution of 1.55 g of 3-chloroperoxybenzoic acid in 5 ml of ethyl acetate in a mixture is added over 5 minutes under argon at -5 ° C. 881 mg of 1 H-pyrrolo [2,3-b] pyridine-4-carboxylic acid methyl ester (which can be obtained according to WO 2003/000688) in 10 ml of ethyl acetate. After stirring for 1 hour at -5 ° C., it is allowed to return to ambient temperature. The brown solid is filtered, washed with 3 times 3 ml of ethyl acetate and dried. 844 mg of 7-oxy-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid methyl ester are obtained in the form of a brown solid whose characteristics are as follows: 60 - Spectrum NMR 1 H: (400MHz, b in ppm, DMSO-d6): 3.93 (s, 3H); 6.93 (d, J = 2.9 Hz, 1H); 7.63 (d, J = 2.9 Hz, 1H); 7.64 (d, J = 6.8 Hz, 1H); 8.23 (d, J = 6.8 Hz, 1H); 12.79 (spread m, 1H). - Mass spectrum (LC / MS Method A): Retention time Tr (min) = 1.97; [M + H] +: m / z 193; [MH] -: m / z 191. Step 2: In a three-necked 100mL while maintaining the temperature under 25 ° C., 2.17 ml of methanesulfonyl chloride are added dropwise to a suspension of methyl ester (4.49 g). 7-oxy-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid obtained according to the preceding step, in 30 mL of dimethylformamide. The reaction medium is then heated at 80 ° C. for 1 hour. After cooling, 2.17 ml of methanesulphonyl chloride are added again while maintaining the temperature under 35 ° C. The reaction medium is heated again at 80 ° C. for 1 hour. After cooling, 50 ml of water are added while maintaining the temperature under 30 ° C. The highly viscous reaction medium is cooled to 5 ° C. and the precipitate is filtered. The beige solid is washed with 5 times 15 ml of water and dried. 3.53 g of 6-chloro-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid methyl ester are obtained in the form of a beige solid, the characteristics of which are as follows: 1H NMR Spectrum: (400MHz, 6 ppm, DMSO-d6): 3.96 (s, 3H); 6.88 (dd, J = 3.4 and 2.0 Hz, 1H); 7.57 (s, 1H); 7.75 (dd, J = 3.4 and 2.5 Hz, 1H); 12.27 (spread m, 1H). Step 3: In a 100mL flask, 7.5mL of a 1M aqueous solution of lithium hydroxide is added at room temperature to a suspension of 527mg of 6-chloro-1H-pyrrolo acid methyl ester. [2,3-b] pyridine-4-carboxylic acid obtained according to the preceding step, in 15 mL of methanol. After stirring for 2.5 hours at room temperature, 7.5 ml of 1N hydrochloric acid are added dropwise. After stirring for 2 hours, the solid is filtered off, washed with 25 ml of water and the mixture is stirred at room temperature. dried. 475 mg of 6-chloro-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid are obtained in the form of a beige solid, the characteristics of which are as follows: 1H NMR spectrum: (400MHz 8 ppm, DMSO-d6): 6.87 (dd, J = 3.4 and 2.0 Hz, 1H); 7.53 (s, 1H); 7.70 (dd, J = 3.4 and 2.5 Hz, 1H); 12.19 (spread m, 1H); 13.66 (very spread m, 1H). Mass Spectrum (LC / MS Method A): Retention Time Tr (min) = 2.35; [M + H] +: m / z 197; [MH] -: m / z 195. Step 4: In a 100 ml flask, a mixture of 69 mg of 5- (3H-imidazo [4,5-c] pyridin-2) is stirred for 3 hours under argon at room temperature. yl) -9H-pyrrolo [1,2-a] indol-9-ylamine obtained according to step 4 of example 3, of 48 mg of 6-chloro-1H-pyrrolo [2,3-b] acid pyridine-4-carboxylic acid obtained according to the preceding step, 51 mg of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI) and 36 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), eluting with a gradient of methanol (4% to 6% v / v) in dichloromethane. The fractions of interest are pooled, evaporated to dryness in vacuo and the residue triturated in sodium bicarbonate solution, filtered and the solid washed with water. The precipitate is dissolved in methanol and the solvent is evaporated to dryness in vacuo. 11 mg of 6- [6- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide from 6- chloro-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid in the form of a solid whose characteristics are the following: 1 H NMR spectrum: (300 MHz, 8 ppm, DMSO-d 6): 6.21 at 6.28 (m, 2H); 6.36 (broad d, J = 8.3 Hz, 1H); 6.91 (d, J = 3.7 Hz, 1H); 7.31 (t, J = 7.8 Hz, 1H); 7.54 (s, 1H); 7.56 to 7.68 (m, 3H); 7.90 (broad d, J = 7.8 Hz, 1H); 8.04 (spread m, 1H); 8.26 (d, J = 6.0 Hz, 1H); 8.96 (s, 1H); 9.43 (d, J = 8.3 Hz, 1H); 12.08 (spread m, 1H). Mass Spectrum (LC / MS Method D): Retention Time Tr (min) = 0.59; [M + H] +: m / z 466; [M-H] -: m / z 464.

Example 5: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g (detail of excipient: lactose, talc, starch, stearate magnesium).

The present invention also includes all pharmaceutical compositions prepared with any product of formula (I) according to the present invention.

Biological Tests for Biologically Characterizing the Products of the Invention: The inorganic phosphate released during the hydrolysis of ATP by the ATPase activity of Hsp82 is quantified by the green malachite method. In the presence of this reagent, there is formation of malachite green-molybdate-inorganic phosphate complex which absorbs at a wavelength of 620 nm.

The products to be evaluated are incubated in a 30 μl reaction volume, in the presence of 1 μM Hsp82 and 250 μM substrate (ATP) in a buffer composed of 50 mM Hepes-NaOH (pH 7.5), 1 mM DU, 5 μM. mM MgCl 2 and 50 mM KCl at 37 ° C for 60 min. In parallel, a range of inorganic phosphate of between 1 and 40 μM is formed in the same buffer.

The ATPase activity is then revealed by the addition of 60 μl of the biomol green (Tebu) reagent. After 20 min of incubation at room temperature, the absorbance of the different wells is measured using a microplate reader at 620 nm. The inorganic phosphate concentration of each sample is then calculated from the calibration curve.

The ATPase activity of Hsp82 is expressed as the concentration of inorganic phosphate produced in 60 minutes. The effect of the various products tested is expressed as percentage inhibition of ATPase activity. The formation of ADP due to the ATPase activity of Hsp82 was used to develop another method for evaluating the enzymatic activity of this enzyme by application of an enzyme coupling system involving pyruvate kinase ( PK) and lactate dehydrogenase (LDH). In this kinetic-type spectrophotometric method, PK catalyzes the formation of ATP and pyruvate from phosphoenol-pyruvate (PEP) and ADP produced by Hsp82. The pyruvate formed, substrate of the LDH, is then converted into lactate in the presence of NADH. In this case, the decrease in NADH concentration as measured by the decrease in absorbance at the wavelength of 340 nm is proportional to the concentration of ADP produced by Hsp82. The tested products are incubated in a reaction volume of 100 μl of buffer composed of 100 mM Hepes-NaOH (pH 7.5), 5 mM MgCl 2, 1 mM DU, 150 mM KCl, 0.3 mM NADH, 2.5 mM PEP and 250 μM ATP. This mixture is preincubated at 37 ° C. for 30 minutes before addition of 3.77 units of LDH and 3.77 units of PK. The reaction is initiated by adding the product to be evaluated, in varying concentrations, and Hsp82, at a concentration of 1 μM. The measurement of the enzymatic activity of Hsp82 is then carried out continuously in a microplate reader at 37 ° C. at the wavelength of 340 nm. The initial speed of the reaction is obtained by measuring the slope of the tangent at the origin of the recorded curve. The enzymatic activity is expressed as pM of ADP formed per minute. The effect of the various products tested is expressed in the ability to inhibit the ATPase activity according to the coding below: A: IC 50 <1 μM B: 1 μM <IC 50 <10 μM C: 10 μM <IC 50 <100 μM Table of results Ex Structure Hsp82 Ex Structure Hsp82 ATPase ATPase IC50 pM IC50 pM 1 NA 2 NBF ~ i \ NH NH NH I 64 NH A 4 NR ~ NH NH N NH NH \ 0 \ O 1 / N CI 10 15 20 25 65

Claims (2)

Claims 1) Products of Formula (I) Het (I) in which: Het represents an aromatic or partially unsaturated 5- or 11-membered dihydro or tetrahydro mono or bicyclic heterocycle containing from 1 to 4 heteroatoms selected from N , O or S, optionally substituted by one or more radicals R1 or R'1 which are identical or different as described below, R is chosen from the group consisting of X- (AB) n-CONH2, X- (AB) n -OCONH 2, X- (AB) n -NH-CONH 2, X- (CH 2) m -heterocycloalkyl, X- (CH 2) m -aryl and X- (CH 2) m -heteroaryl with X is -OC (O), - NH-C (O), NH-CS, -NHCO-CH 2 -O-; -NH-CO-CH 2 -S-CH 2 -CO-NH-; -NH-CO- (CH 2) 2 -SO 2 -; -NH-CO-CH2-N (CH3) -CO-; A and B, which are identical or different, independently represent a single bond, CH2, CH-alkyl, CH-aralkyl, n = 1,2 and m = 0, 1, R1 and / or R'1, which may be identical or different, are in the group consisting of H, halogen, CF3, nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxy free or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl) 2, NH-CO-alkyl, sulfonamide, NHSO 2 -alkyl, S (O) 2 -NHalkyl, S (O 2) -N (alkyl) 2, all the alkyl, alkoxy and alkylthio radicals being themselves optionally substituted with one or more radicals identical or different selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; said products of formula (I) being in all possible tautomeric and isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as as addition salts with inorganic and organic acids or with the inorganic and organic bases of the products of formula (I) as well as the prodrugs of the products of general formula (I). 2) Products of formula (I) as defined in claim 1 in which: Het is chosen from the group consisting of: R11N N ù NHR 'R1 HZN N HZN N HOC I Ni MeO ~ v \ N ~ i N - N ~ N \ / Nv ~ NNISHH RI and / or R'1 identical or different are in the group consisting of H, halogen, CF3, nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio ( methylthio), carboxy free or esterified with alkyl, carboxamide, CO-NH (alkyl) and CON (alkyl) 2, NH-CO-alkyl, sulfonamide, NH-SO 2 -alkyl, S (O) 2 -NH (alkyl) ), S (O) 2-N (alkyl) 2, all the alkyl, alkoxy and alkylthio radicals themselves being optionally substituted by one or more identical or different radicals selected from halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino; the substituent R of said products of formula (I) being chosen from the values defined in any one of the other claims, said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomers and diastereoisomers, as well as as addition salts with the inorganic and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the prodrugs of the products of general formula (I). 67) Products of formula (I) as defined in any one of the other claims in which Het represents a heterocycle as defined in claim 1 or 2 optionally substituted by one or more radicals R1 or R'1 or R "1 same or different as defined in any one of the other claims, and R is selected from the group consisting of: NH NH NH NH NH NH NH NH NH NH NH NH said products of formula (I) being in all possible tautomeric and isomeric forms, racemic, enantiomers and diastereoisomers, as well as as addition salts with mineral and organic acids or with the inorganic and organic bases of the products of formula (I ) as well as the prodrugs of the products of general formula (I) 68) Products of formula (I) as defined in any one of the other claims in which: Het is selected from the group consisting of: R1 H2NNi R is chosen in the group consisting of: ## STR2 ## is in the group consisting of H, F, Cl, Br, CF 3, NO 2, CN, CH 3, OH, OCH 3, OCF 3, CO2Me, CONH 2, CONHMe, CONH- (CH2) 3-OMe, CONH-10 (CH2) 3-N (Me) 2, NHC (O) Me, SO2NH2, SO2N (Me) 2; R'1 is in the group consisting of H, CONH2, CONHMe and OMe; R "1 is in the group consisting of F, Cl, OH, OMe, CN, O- (CH2) 3-OMe and O- (CH2) 3-N (Me) 2, said products of formula (I) being all possible tautomeric and isomeric forms, racemic, enantiomeric and diastereomeric, as well as as addition salts with mineral and organic acids or with the inorganic and organic bases of the products of formula (I), as well as the prodrugs of the products of general formula (I) 5) Products of formula (I) as defined in any one of the other claims in which: Het is selected from the group consisting of: 69R'1 1 NNH R1 \ ~ R is selected from the group consisting of: ## STR2 ## in the group consisting of H, F, Cl, Br, CF 3, NO 2, CN, CH 3, OH, OCH 3, OCF 3, CO2Me, CONH 2, CONHMe , CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC (O) Me, SO2NH2, SO2N (Me) 2, R'1 is in the group consisting of H, CONH2, CONHMe and OMe, R "1 is in the group consisting of F, Cl, OH, OMe, CN, O- (CH) 2) 3-OMe and O- (CH 2) 3 -N (Me) 2 said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral and organic bases. 6) Products of formula (I) as defined in any one of the other claims in which: Het is selected from the group consisting of: R1 - -N 1 NNH R1 with ~ MeO ~~ '\ N' 70RI is H, F, Cl, Br, CF3, NO2, CN, CH3, OH, OCH3, OCF3, CO2Me, CONH2, CONHMe, CONH- (CH2) 3-OMe, CONH- (CH2) 3-N (Me) 2, NHC (0) Me, SO2NH2, SO2N (Me) 2; R'1 represents H, CONH2, CONHMe and OMe; R "1 represents F, Cl, OH, OMe, CN, O- (CH 2) 3-OMe and O- (CH 2) 3 -N (Me) 2, and R is selected from the group consisting of: NH NH NH CI as well as their prodrugs, said products of formula (I) being in all the possible isomeric forms tautomers, racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I) 7) Products of formula (I) as defined in any of the other claims whose names follow: - [5- (6-fluoro-1H-benzimidazol-2-yl) 1 H -pyrrolo [2,3-b] pyridine-4-carboxylic acid-9H-pyrrolo [1,2-a] indol-9-yl] amide 5-quinolin-3-yl 1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid 1H-pyrrolo [1,2-a] indol-9-yl) -amide - [5- (3H-imidazo [4H]) 5-c] pyridin-2-yl) -9H-pyrrolo [1,2-a] indol-9-yl] -amide of 1H-pyrrolo [2,3-b] pyridine-4- acid carboxylic acid - [5- (3H-imidazo [4,5-c] pyridin-2-yl) -9H-pyrrolo [1,2-aji] 6-chloro-1H-pyrrolo [2,3-b] pyridine-4-carboxylic acid ndol-9-yl] -amide. As well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 8) Process for the preparation of the products of formula (I) as defined in the preceding claims, characterized by scheme (I) below: according to which the products of general formula (I) can be prepared from a derivative of general formula (II), either via a derivative of general formula (III) (method A) or via a derivative of general formula (IV) (method B) according to the general scheme (1) below: Het Het method B (IV) Z = OTf, I, Br, B (OH) 2 or B (OR) 2 * or C (O) -OMe, C (O) -OH or C (0) -H) or OH or O-CHZ Ph * B (OR) 2 capable of forming a ring Scheme (1) in which the substituents Het and R have the meanings indicated for the products of formula (I) as defined in the preceding claims and za the meaning indicated above in Scheme (1), 9) As new industrial products, the synthetic intermediates of formulas (II), (III) and (IV): 72 (II) ) (III) Het Z = OTf, I, Br, B (OH) 2 or B (OR) 2 * or C (O) -OMe, C (O) -OH or C (O) -H) or OH or O -CH 2 Ph * B (OR) 2 which can form a ring compounds of formulas (II), (III) and (IV) in which the substituents Het and R have the meanings indicated for the products of formula (I) in one any of the other claims and za the meaning indicated above, excluding the compound of formula (II) wherein z represents an iodine atom. 10) As medicaments, the products of formula (I) as defined in claims 1 to 7), and their prodrugs, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 11) As medicaments, the products of formula (I) as defined in claim 6), as well as their prodrugs, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 73) As medicaments, the products of formula (I) as defined in claim 7), as well as their prodrugs, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 13) Pharmaceutical compositions containing as active principle, at least one of the medicaments as defined in claims 10 to 12. 14) Pharmaceutical compositions as defined in the preceding claim 10 additionally containing active ingredients of other chemotherapy drugs against cancer. 15) Pharmaceutical compositions according to any one of the preceding claims, characterized in that they are used as medicaments, in particular for the chemotherapy of cancers. 16) Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for preventing or treating a disease belonging to the following group: neurodegenerative diseases such as Huntington's disease, Parkinson's disease, focal cerebral ischemia, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis, malaria, Brugia filariasis and Bancroft, toxoplasmosis, treatment-resistant mycoses, hepatitis B, hepatitis C, herpes virus, dengue (or tropical flu), spinal and bulbar muscular atrophy, proliferative disorders mesangial cells, thromboses, retinopathies, psoriasis, muscle degeneration, diseases in oncology, cancers. 17) Use of products of formula (I) as defined in any one of the preceding claims or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating cancers. 74) Use of products of formula (I) according to the preceding claim wherein the disease to be treated is a cancer of solid or liquid tumors. 19) Use of products of formula (I) according to the preceding claim 5 wherein the disease to be treated is a cancer resistant to cytotoxic agents. 20) Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating cancers among which cancers lung, breast and ovary, glioblastomas, chronic myeloid leukemias, acute lymphoblastic leukemias, prostate, pancreatic and colon cancers, metastatic melanomas, thyroid tumors and renal carcinomas. 21) Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for the chemotherapy of cancers. 22) Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments for the chemotherapy of cancers used alone or in combination . 23) Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments for use alone or in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents. 24) Use of products of formula (I) according to the preceding claim wherein the therapeutic agents may be commonly used anti-tumor agents. 75) Products of formula (I) as defined in any one of the preceding claims as inhibitors of HSP90, said products of formula (I) being in all possible tautomeric and / or isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I) as well as their prodrugs. 76